Alzheimer’s disease has been linked to mutations in a gene encoding the amyloid precursor protein (APP). Mutations in this gene cause early onset Alzheimer’s disease in some families. Studies in animals suggest this mutant form of the protein may interfere with the messages sent between brain cells. But it remains unclear how this protein works even when it isn’t mutated.

One reason it has been difficult to figure out how APP works is because it is a long protein and is often cut into smaller, but still functional proteins. It is unclear which parts of the protein are involved in sending messages between brain cells, but previous research has allowed scientists to zero in on one stretch of the protein containing just 50 amino acids.

Now, Fanutza, Del Prete et al. reveal that this short stretch of APP interacts with the proteins that control the release of glutamate, one of the brain’s most important excitatory neurotransmitter. This stretch is cut from the full protein and released into the cell as a protein fragment (or peptide). Further experiments showed that this naturally occurring peptide interferes with the activity of APP, and in doing so reduces the release of glutamate from brain cells in mice. However, there was no effect on glutamate release when this peptide was introduced inside brain cells from mutant mice that lacked APP.

Together, the results show that this 50-amino acid stretch of APP promotes glutamate release between brain cells, and that a peptide containing the same stretch of the protein interferes with this process. Altered glutamate neurotransmission could explain the memory loss and thinking problems seen in early Alzheimer’s disease. Therefore, drug treatments that aim to restore normal glutamate transmission may prove a beneficial therapeutic strategy in Alzheimer’s disease.

Human genetic evidence and studies in App-knock-out (KO) mice indicate that the amyloid precursor protein (APP) plays an important physiological role in the central nervous system. In humans, a polymorphism in APP that reduces APP processing protects from sporadic Alzheimer’s disease (AD) and normal aging-dependent cognitive decline (De Strooper and Voet, 2012, Jonsson et al., 2012). In contrast, mutations in APP and in genes that regulate APP processing – such as PSENs and BRI2/ITM2B – cause familial AD (FAD) and the AD-like familial British dementia and familial Danish dementia (De Strooper, 2007, De Strooper et al., 2010, De Strooper and Voet, 2012, Garringer et al., 2010, Matsuda et al., 2005, Giliberto et al., 2008, Matsuda et al., 2009, Tanzi, 2012, Vidal et al., 1999, 2000). Analysis of App-KO mice has also suggested a synaptic role for APP (Korte et al., 2012, Marcello et al., 2012, Octave et al., 2013, Randall et al., 2010, Turner et al., 2003, Venkitaramani et al., 2007). For example, hippocampal App-KO neurons in culture show enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission and increased size of the readily releasable synaptic vesicle pool (RRP). In addition, long-term potentiation (LTP), a form of synaptic plasticity that underlies memory formation, is impaired in App-KO mice; and these LTP deficits are clearly noticeable in aged but not in juvenile App-KO mice (Dawson et al., 1999, Korte et al., 2012, Priller et al., 2006, Venkitaramani et al., 2007).

Although the evidence indicating that APP plays a role in several processes controlling synaptic function is strong, the molecular mechanisms are poorly understood. A confounding factor when studying APP function is the complex APP metabolism. The best-characterized cascade involves a sequential β/γ-secretase cleavage of APP. In this pathway, APP is cleaved by β-secretase/BACE1 into a soluble ectodomain (sAPPβ) and a membrane-bound COOH-terminal fragment of 99 amino acids (C99 or β C-terminal fragment [CTF]). C99/β-CTF is cleaved by the γ-secretase to produce Aβ peptides, which are believed to be the main culprit of AD, and the APP intracellular domain (AID/AICD). Alternatively, α-secretase cleaves APP in the Aβ sequence into sAPPα and a membrane-bound COOH-terminal fragment of 83 amino acids (C83 or α-CTF). C83/α-CTF is cleaved by the γ-secretase to produce a short peptide comprising the COOH-terminus of Aβ, called P3, and AID/AICD (Annaert et al., 2000, De Strooper, 2003, Selkoe and Kopan, 2003, Sisodia and St George-Hyslop, 2002, Vassar et al., 1999). Another processing pathway, potentially important yet less studied, involves cleavage of APP in the cytoplasmic domain – between D⁶⁶⁴ and A⁶⁶⁵, following the numbering of the main brain APP isoform of 695 amino acids – by caspase-6, -3, and -8. Caspases can in theory process all APP metabolites comprising this intracellular motif, such as full-length APP, C99/β-CTF, C83/α-CTF, and AID/AICD. So far, cleavages of full-length APP and AID/AICD by caspases have been described (Bertrand et al., 2001, Gervais et al., 1999, Lu et al., 2000, Madeira et al., 2005, Pellegrini et al., 1999, Weidemann et al., 1999). Processing of full-length APP generates a membrane bound NH₂-terminal fragment called APP-Ncas and a COOH-terminal intracellular peptide called APP-Ccas or C31 (Bertrand et al., 2001, Gervais et al., 1999, Lu et al., 2000, Madeira et al., 2005, Pellegrini et al., 1999, Weidemann et al., 1999). Caspase cleavage of AID/AICD splits the cytoplasmic domain of APP into two soluble cytosolic peptides: the aforementioned Ccas/C31 and JCasp. The latter comprises the NH₂-terminal peptide segment of the APP intracellular domain (Bertrand et al., 2001, Madeira et al., 2005). Recently, a new secretase activity (called η-secretase) has been described (Willem et al., 2015). Cleavage by η-secretase occurs primarily at amino acids 504–505 of APP695 and releases a ~500 amino acid-long ecto-domain and a membrane-bound fragment called CTF-η. Interestingly, CTF-η is further processed by α- and β-secretases to release a long and a short Aη peptide (Aη-α and Aη-β, respectively).

Many of the APP metabolites produced by these cleavages are biologically active. AID/AICD modulates programmed cell death, gene transcription and Ca²⁺ homeostasis (Baek et al., 2002, Cao and Südhof, 2001, Checler et al., 2007, Cupers et al., 2001, Hamid et al., 2007, Kim et al., 2003, Leissring et al., 2002, Liu et al., 2007, Madeira et al., 2005, Pardossi-Piquard et al., 2005, Passer et al., 2000, von Rotz et al., 2004). The caspase-derived APP fragments Ccas/C31 and JCasp (Bertrand et al., 2001, Lu et al., 2000, Madeira et al., 2005) also possess toxic activities. Aβ both regulates normal synaptic transmission and prompts deficits in synaptic plasticity (Fogel et al., 2014, Mota et al., 2014, Puzzo and Arancio, 2013, Puzzo et al., 2008, Shankar et al., 2007, Sivanesan et al., 2013, Um et al., 2012). sAPPα has neurotrophic functions and is involved in synaptic plasticity (Hick et al., 2015, Milosch et al., 2014). sAPPβ promotes axon pruning and neurodegeneration (Nikolaev et al., 2009). Aη-α can reduce LTP (Willem et al., 2015). β-CTF mediates long-term synaptic plasticity deficits, behavioral deficits and neurodegeneration (Neve et al., 1996, Neve and Robakis, 1998, Oster-Granite et al., 1996, Tamayev et al., 2012b, 2012c).

The presence of the functionally redundant APP-like protein-1 and -2 (APLP1 and APLP2) is another confounding factor. APLP1 and APLP2 are processed like APP (Heber et al., 2000, Herms et al., 2004, Müller and Zheng, 2012, Scheinfeld et al., 2002, von Koch et al., 1997) and release intracellular peptides – called APLP2-intracellular domain (ALID) 1 and ALID2, respectively – that, like AID/AICD, can potentially regulate transcription (Scheinfeld et al., 2002, 2003). The evidence that Aplp2-KO and App-KO mice are viable, whereas combined App/Aplp2-dKO mice develop neuromuscular junction deficits and die shortly after birth (Wang et al., 2005) vividly illustrates the functional redundancy of APP and APLP2. The robust phenotype of App/Aplp2-dKO mice can be used to map the functional domains of APP by expressing App knock-in mutations on an Aplp2-KO genetic background. This in vivo functional mapping has identified an essential role for the highly conserved APP intracellular domain in the patterning of neuromuscular junction and survival (Barbagallo et al., 2011a, 2011b, Li et al., 2010), indicating that the intracellular region of APP is functionally important in vivo

The APP cytoplasmic domain is very short (~50 amino acids) and does not possess recognizable enzymatic domains, raising the possibility that APP functions could be dictated by molecular interaction of the APP cytoplasmic domain with intracellular proteins. Using an unbiased proteomic approach, we found that the brain APP intracellular domain-interactome includes synaptic vesicles trans-membrane proteins, proteins associated with synaptic vesicles and the presynaptic active zone (Del Prete et al., 2014). Many of these proteins, such as cis- and trans-SNAREs, complexin, and the Ca²⁺ sensors synaptotagmins, function as key regulators of synaptic vesicles exocytosis (McMahon and Boucrot, 2011, Rizzoli, 2014, Royle and Lagnado, 2010, Südhof, 2012, 2013, Südhof and Rizo, 2011, Xu et al., 2009). Remarkably a similar brain APP–presynaptic interactome was identified in transgenic mice overexpressing human APP (Kohli et al., 2012, Norstrom et al., 2010). These findings are consistent with the evidence that APP in the brain is found at presynaptic terminals and synaptic vesicles (Del Prete et al., 2014, Groemer et al., 2011, Laßek et al., 2014, Wilhelm et al., 2014, Yang et al., 2005).

The fact that APP is present at synaptic vesicles and the presynaptic active zone – specialized region of the presynaptic membrane where neurotransmitter release occurs – and that the APP intracellular domain interacts with the neurotransmitter release machinery suggests that APP regulates transmitter release. Here, we investigated this proposition. By recording neuronal activity in hippocampal brain slices while using and APP-derived peptide that interferes with the APP-neurotransmitter release machinery interaction and acts as a dominant negative inhibitor of APP, we implicate APP in the physiological regulation of the synaptic release of glutamate at hippocampal excitatory synapses. Moreover, we found that APLP2 can compensate for loss of APP function and that genetic ablation of both APP and APLP2 protein expression produces glutamatergic synaptic transmission deficits similar to those caused by JCasp, confirming that JCasp acts as a dominant negative inhibitor of some functions of APP in wild-type (WT) animals. Our results indicate that APP and APLP2 fine-tune synaptic vesicle release likely through the interaction with, and regulation of, the molecular machinery that controls synaptic vesicle exocytosis.

Using an unbiased proteomic methodology and competition experiments, we found that the NH₂-terminal activation-induced cytidine deaminase (AID) region, JCasp, is the APP domain that binds presynaptic proteins regulating synaptic transmission. We have used a peptide encompassing this JCasp region to test whether the interaction of APP with proteins that regulate synaptic vesicles exocytosis enables APP to tune synaptic vesicles release. Strikingly, intracellular delivery of JCasp caused a strong reduction in basal synaptic transmission. Consistent with a presynaptic action, this reduction was associated with an increase in PPF and FF, as well as in mEPCS frequency but not amplitude, rise time, and decay time. These effects are evident in WT synapses but absent at APP-lacking synapses. In addition, Pen1-JCasp reduced the rate of synaptic vesicles depletion without affecting recycling. Taken together, these results indicate that JCasp acts as a dominant negative inhibitor of APP, and that APP facilitates the release of excitatory synaptic vesicles, likely via the interaction with and functional regulation of the molecular machinery that controls synaptic vesicles exocytosis.

The evidence that glutamatergic synaptic vesicles release is normal in the hippocampus of young App-KO mice suggests that compensatory mechanisms counterbalance the loss of APP function. Given the functional redundancy of APP and APLP2 in neuromuscular junctions patterning and survival (Barbagallo et al., 2011b, Li et al., 2010, Wang et al., 2005), we thought that APLP2 could compensate for loss of APP function at hippocampal synapse. Consistent with this hypothesis, we found that the intracellular domain of APLP2, ALID2, interacts with key regulators of synaptic vesicle exocytosis. A systematic characterization of SC–CA1 synaptic transmission revealed that APP and APLP2 have redundant functions in the hippocampus as indicated by the following observations: 1) App-KO animals showed normal synaptic transmission at SC–CA1 excitatory synapses; 2) Aplp2-KO mice presented a significant reduction in mEPSCs frequency; 3) App/Aplp2-dKO mice showed increased PPF and FF, which was not observed in single App-KO and Aplp2-KO mice, as well as reduced mEPSCs frequency.

Overall, the synaptic phenotype observed in App/Aplp2-dKO mice is very similar to that induced by Pen1-JCasp in WT animals, suggesting a primary functional role for the intracellular domains of APP and APLP2 in tuning glutamate release. A notable exception is represented by an increase in mEPSC decay time – present in App/Aplp2-dKO mice but not in hippocampal slices incubated with Pen1-JCasp. This observation suggests that Pen1-JCasp can unveil the role of the JCasp domain of APP without directly affecting the function of other APP region, such as, for example, Aβ or the APP extracellular domain.

Our results indicate that JCasp is an inhibitor of APP but not APLP2. This specificity of JCasp for APP allows to study the function of the APP intracellular domain in WT adult animals, eliminating the confounding effects associated with both constitutive and conditional App-KO models. In fact, it permits acute inhibition of the functions of this APP domain in WT adult animals, circumventing developmental issues and compensatory mechanisms, such as those mediated by APLP2 and/or APLP1. The results presented here indicate that APP and APLP2 facilitate the release of excitatory synaptic vesicles, likely via the interaction with and functional regulation of the molecular machinery that controls synaptic vesicle exocytosis. How exactly these presynaptic APP interactions tune vesicles exocytosis and how this function is regulated remain to be elucidated.

While a recent study in primary neuronal cells has shown that Aβ can increase Pr by enhancing presynaptic Ca⁺² influx (Fogel et al., 2014), our findings support a Ca⁺² influx-independent mechanism. These two mechanisms of action of APP are not mutually exclusive and could act synergistically to control neurotransmitter release. Inherited or acquired factors leading to altered APP metabolism and Aβ levels could negatively impact this physiological function of APP and, eventually, contribute to the pathogenesis of AD.

It is worth noting that AID/AICD and JCasp are natural proteolytic products of APP. The mechanisms by which cleavage of APP can regulate synaptic transmission are twofold; 1) severing the APP–presynaptic multi-molecular complex from membranes; and 2) liberating cytosolic proteolysis fragments of APP, such as AID/AICD and JCasp, which could act, as we show for Pen1-JCasp, as dominant negative inhibitors of APP. AID/AICD and JCasp have very short half-lives and are hardly detectable in vivo (Cupers et al., 2001, Giliberto et al., 2010, 2008, Passer et al., 2000). It therefore appears that evolution has selected mechanisms, which are perhaps expensive in terms of genetic information and energy usage, to tightly regulate the levels of AID/JCasp, suggesting that AID/AICD and JCasp are biologically active and need to be strictly controlled.

APP plays a central role in the pathogenesis of both sporadic AD and FAD. Many previous studies investigating synaptic dysfunction induced by Aβ, which derives from APP processing and is considered the main mediator of AD pathogenesis, have suggested that early pathogenic changes in AD were driven by postsynaptic impairments (Cissé et al., 2011, Ferreira et al., 2012, Li et al., 2009, Mucke and Selkoe, 2012, Parameshwaran et al., 2008, Roberson et al., 2011, Shankar et al., 2007, Um et al., 2012). However, the presynaptic function of APP described here , together with evidence that the other familial Alzheimer’s proteins PS1 and PS2 regulate glutamate release in mature neurons by a presynaptic mechanism (Fogel et al., 2014, Wu et al., 2013, Xia et al., 2015, Zhang et al., 2009), support the possibility that deficits in neurotransmitter release represents a convergent mechanism involved in AD.

1. 1. Annaert WIM
   2. Cupers P
   3. Saftig P
   4. Strooper B

   (2000) Presenilin function in APP processing

   Annals of the New York Academy of Sciences 920:158–164.

   https://doi.org/10.1111/j.1749-6632.2000.tb06917.x

   • Google Scholar
2. 1. Baek SH
   2. Ohgi KA
   3. Rose DW
   4. Koo EH
   5. Glass CK
   6. Rosenfeld MG

   (2002) Exchange of n-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein

   Cell 110:55–67.

   https://doi.org/10.1016/S0092-8674(02)00809-7

   • Google Scholar
3. 1. Barbagallo APM
   2. Wang Z
   3. Zheng H
   4. D'Adamio L
   5. Ginsberg S

   (2011a) The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function

   PLoS ONE 6:e18006.

   https://doi.org/10.1371/journal.pone.0018006

   • Google Scholar
4. 1. Barbagallo APM
   2. Wang Z
   3. Zheng H
   4. D'Adamio L

   (2011b) A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function

   Journal of Biological Chemistry 286:8717–8721.

   https://doi.org/10.1074/jbc.C111.219873

   • Google Scholar
5. 1. Bertrand E
   2. Brouillet E
   3. Caillé I
   4. Bouillot C
   5. Cole GM
   6. Prochiantz A
   7. Allinquant B

   (2001) A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo

   Molecular and Cellular Neuroscience 18:503–511.

   https://doi.org/10.1006/mcne.2001.1030

   • Google Scholar
6. 1. Cao X
   2. Südhof TC

   (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60

   Science 293:115–120.

   https://doi.org/10.1126/science.1058783

   • Google Scholar
7. 1. Checler F
   2. Sunyach C
   3. Pardossi-Piquard R
   4. Sevalle J
   5. Vincent B
   6. Kawarai T
   7. Girardot N
   8. George-Hyslop PS
   9. da Costa C

   (2007) The gamma/epsilon-secretase-derived APP intracellular domain fragments regulate p53

   Current Alzheimer Research 4:423–426.

   https://doi.org/10.2174/156720507781788945

   • Google Scholar
8. 1. Cissé M
   2. Halabisky B
   3. Harris J
   4. Devidze N
   5. Dubal DB
   6. Sun B
   7. Orr A
   8. Lotz G
   9. Kim DH
   10. Hamto P
   11. Ho K
   12. Yu GQ
   13. Mucke L

   (2011) Reversing EphB2 depletion rescues cognitive functions in alzheimer model

   Nature 469:47–52.

   https://doi.org/10.1038/nature09635

   • Google Scholar
9. 1. Cupers P
   2. Orlans I
   3. Craessaerts K
   4. Annaert W
   5. De Strooper B

   (2001) The amyloid precursor protein (aPP)-cytoplasmic fragment generated by γ-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture

   Journal of Neurochemistry 78:1168–1178.

   https://doi.org/10.1046/j.1471-4159.2001.00516.x

   • Google Scholar
10. 1. Davidson TJ
    2. Harel S
    3. Arboleda VA
    4. Prunell GF
    5. Shelanski ML
    6. Greene LA
    7. Troy CM

    (2004) Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation

    The Journal of Neuroscience 24:10040–10046.

    https://doi.org/10.1523/JNEUROSCI.3643-04.2004

    • Google Scholar
11. 1. Dawson GR
    2. Seabrook GR
    3. Zheng H
    4. Smith DW
    5. Graham S
    6. O'Dowd G
    7. Bowery BJ
    8. Boyce S
    9. Trumbauer ME
    10. Chen HY
    11. Van der Ploeg LHT
    12. Sirinathsinghji DJS

    (1999) Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein

    Neuroscience 90:1–13.

    https://doi.org/10.1016/S0306-4522(98)00410-2

    • Google Scholar
12. 1. De Strooper B

    (2003) Aph-1, pen-2, and nicastrin with presenilin generate an active γ-secretase complex

    Neuron 38:9–12.

    https://doi.org/10.1016/S0896-6273(03)00205-8

    • Google Scholar
13. 1. De Strooper B

    (2007) Loss-of-function presenilin mutations in alzheimer disease. talking point on the role of presenilin mutations in alzheimer disease

    EMBO Reports 8:141–146.

    https://doi.org/10.1038/sj.embor.7400897

    • Google Scholar
14. 1. De Strooper B
    2. Vassar R
    3. Golde T

    (2010) The secretases: enzymes with therapeutic potential in alzheimer disease

    Nature Reviews. Neurology 6:99–107.

    https://doi.org/10.1038/nrneurol.2009.218

    • Google Scholar
15. 1. De Strooper B
    2. Voet T

    (2012) Alzheimer's disease: a protective mutation

    Nature 488:38–39.

    https://doi.org/10.1038/488038a

    • Google Scholar
16. 1. Del Prete D
    2. Lombino F
    3. Liu X
    4. D'Adamio L

    (2014) APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions

    PloS One 9:e108576.

    https://doi.org/10.1371/journal.pone.0108576

    • Google Scholar
17. 1. Ferreira IL
    2. Bajouco LM
    3. Mota SI
    4. Auberson YP
    5. Oliveira CR
    6. Rego AC

    (2012) Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing n-methyl-d-aspartate receptors in cortical cultures

    Cell Calcium 51:95–106.

    https://doi.org/10.1016/j.ceca.2011.11.008

    • Google Scholar
18. 1. Fogel H
    2. Frere S
    3. Segev O
    4. Bharill S
    5. Shapira I
    6. Gazit N
    7. O'Malley T
    8. Slomowitz E
    9. Berdichevsky Y
    10. Walsh DM
    11. Isacoff EY
    12. Hirsch JA
    13. Slutsky I

    (2014) APP homodimers transduce an amyloid-beta-mediated increase in release probability at excitatory synapses

    Cell Reports 7:1560–1576.

    https://doi.org/10.1016/j.celrep.2014.04.024

    • Google Scholar
19. 1. Garringer HJ
    2. Murrell J
    3. D'Adamio L
    4. Ghetti B
    5. Vidal R

    (2010) Modeling familial british and danish dementia

    Brain Structure & Function 214:235–244.

    https://doi.org/10.1007/s00429-009-0221-9

    • Google Scholar
20. 1. Gervais FG
    2. Xu D
    3. Robertson GS
    4. Vaillancourt JP
    5. Zhu Y
    6. Huang J
    7. LeBlanc A
    8. Smith D
    9. Rigby M
    10. Shearman MS
    11. Clarke EE
    12. Zheng H
    13. Van Der Ploeg LHT
    14. Ruffolo SC
    15. Thornberry NA
    16. Xanthoudakis S
    17. Zamboni RJ
    18. Roy S
    19. Nicholson DW

    (1999) Involvement of caspases in proteolytic cleavage of alzheimer’s amyloid-beta precursor protein and amyloidogenic a peptide formationn

    Cell 97:395–406.

    https://doi.org/10.1016/S0092-8674(00)80748-5

    • Google Scholar
21. 1. Giliberto L
    2. Zhou D
    3. Weldon R
    4. Tamagno E
    5. De Luca P
    6. Tabaton M
    7. D'Adamio L

    (2008) Evidence that the amyloid beta precursor protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional role

    Molecular Neurodegeneration 3:12.

    https://doi.org/10.1186/1750-1326-3-12

    • Google Scholar
22. 1. Giliberto L
    2. d'Abramo C
    3. Acker CM
    4. Davies P
    5. D'Adamio L

    (2010) Transgenic expression of the amyloid-beta precursor protein-intracellular domain does not induce alzheimer's disease-like traits in vivo

    PloS One 5:e11609.

    https://doi.org/10.1371/journal.pone.0011609

    • Google Scholar
23. 1. Groemer TW
    2. Thiel CS
    3. Holt M
    4. Riedel D
    5. Hua Y
    6. Hüve J
    7. Wilhelm BG
    8. Klingauf J

    (2011) Amyloid precursor protein is trafficked and secreted via synaptic vesicles

    PloS One 6:e18754.

    https://doi.org/10.1371/journal.pone.0018754

    • Google Scholar
24. 1. Gu Z
    2. Liu W
    3. Yan Z

    (2009) {beta}-amyloid impairs AMPA receptor trafficking and function by reducing Ca2+/calmodulin-dependent protein kinase II synaptic distribution

    The Journal of Biological Chemistry 284:10639–10649.

    https://doi.org/10.1074/jbc.M806508200

    • Google Scholar
25. 1. Guo Q
    2. Li H
    3. Gaddam SS
    4. Justice NJ
    5. Robertson CS
    6. Zheng H

    (2012) Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives

    The Journal of Biological Chemistry 287:2437–2445.

    https://doi.org/10.1074/jbc.M111.315051

    • Google Scholar
26. 1. Hamid R
    2. Kilger E
    3. Willem M
    4. Vassallo N
    5. Kostka M
    6. Bornhövd C
    7. Reichert AS
    8. Kretzschmar HA
    9. Haass C
    10. Herms J

    (2007) Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content

    Journal of Neurochemistry 102:1264–1275.

    https://doi.org/10.1111/j.1471-4159.2007.04627.x

    • Google Scholar
27. 1. Heber S
    2. Herms J
    3. Gajic V
    4. Hainfellner J
    5. Aguzzi A
    6. Rülicke T
    7. von Kretzschmar H
    8. von Koch C
    9. Sisodia S
    10. Tremml P
    11. Lipp HP
    12. Wolfer DP
    13. Müller U

    (2000)

    Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members

    The Journal of Neuroscience 20:7951–7963.

    • Google Scholar
28. 1. Herms J
    2. Anliker B
    3. Heber S
    4. Ring S
    5. Fuhrmann M
    6. Kretzschmar H
    7. Sisodia S
    8. Müller U

    (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members

    The EMBO Journal 23:4106–4115.

    https://doi.org/10.1038/sj.emboj.7600390

    • Google Scholar
29. 1. Hick M
    2. Herrmann U
    3. Weyer SW
    4. Mallm JP
    5. Tschäpe JA
    6. Borgers M
    7. Mercken M
    8. Roth FC
    9. Draguhn A
    10. Slomianka L
    11. Wolfer DP
    12. Korte M
    13. Müller UC

    (2015) Acute function of secreted amyloid precursor protein fragment APPsalpha in synaptic plasticity

    Acta Neuropathologica 129:21–37.

    https://doi.org/10.1007/s00401-014-1368-x

    • Google Scholar
30. 1. Hsieh H
    2. Boehm J
    3. Sato C
    4. Iwatsubo T
    5. Tomita T
    6. Sisodia S
    7. Malinow R

    (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss

    Neuron 52:831–843.

    https://doi.org/10.1016/j.neuron.2006.10.035

    • Google Scholar
31. 1. Jonsson T
    2. Atwal JK
    3. Steinberg S
    4. Snaedal J
    5. Jonsson PV
    6. Bjornsson S
    7. Stefansson H
    8. Sulem P
    9. Gudbjartsson D
    10. Maloney J
    11. Hoyte K
    12. Gustafson A
    13. Liu Y
    14. Lu Y
    15. Bhangale T
    16. Graham RR
    17. Huttenlocher J
    18. Bjornsdottir G
    19. Andreassen OA
    20. Jönsson EG
    21. Palotie A
    22. Behrens TW
    23. Magnusson OT
    24. Kong A
    25. Thorsteinsdottir U
    26. Watts RJ
    27. Stefansson K

    (2012) A mutation in APP protects against alzheimer's disease and age-related cognitive decline

    Nature 488:96–99.

    https://doi.org/10.1038/nature11283

    • Google Scholar
32. 1. Kim HS
    2. Kim EM
    3. Lee JP
    4. Park CH
    5. Kim S
    6. Seo JH
    7. Chang KA
    8. Yu E
    9. Jeong SJ
    10. Chong YH
    11. Suh YH

    (2003) C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression

    FASEB Journal  17:1951–1953.

    https://doi.org/10.1096/fj.03-0106fje

    • Google Scholar
33. 1. Kohli BM
    2. Pflieger D
    3. Mueller LN
    4. Carbonetti G
    5. Aebersold R
    6. Nitsch RM
    7. Konietzko U

    (2012) Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with synaptotagmin-1

    Journal of Proteome Research 11:4075–4090.

    https://doi.org/10.1021/pr300123g

    • Google Scholar
34. 1. Korte M
    2. Herrmann U
    3. Zhang X
    4. Draguhn A

    (2012) The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models

    Experimental Brain Research 217:435–440.

    https://doi.org/10.1007/s00221-011-2894-6

    • Google Scholar
35. 1. Lassek M
    2. Weingarten J
    3. Einsfelder U
    4. Brendel P
    5. Müller U
    6. Volknandt W

    (2013) Amyloid precursor proteins are constituents of the presynaptic active zone

    Journal of Neurochemistry 127:48–56.

    https://doi.org/10.1111/jnc.12358

    • Google Scholar
36. 1. Lassek M
    2. Weingarten J
    3. Acker-Palmer A
    4. Bajjalieh S
    5. Muller U
    6. Volknandt W

    (2014) Amyloid precursor protein knockout diminishes synaptic vesicle proteins at the presynaptic active zone in mouse brain

    Current Alzheimer Research 11:971–980.

    https://doi.org/10.2174/1567205011666141107152458

    • Google Scholar
37. 1. Leissring MA
    2. Murphy MP
    3. Mead TR
    4. Akbari Y
    5. Sugarman MC
    6. Jannatipour M
    7. Anliker B
    8. Müller U
    9. Saftig P
    10. De Strooper B
    11. Wolfe MS
    12. Golde TE
    13. LaFerla FM

    (2002) A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP

    Proceedings of the National Academy of Sciences of the United States of America 99:4697–4702.

    https://doi.org/10.1073/pnas.072033799

    • Google Scholar
38. 1. Li S
    2. Hong S
    3. Shepardson NE
    4. Walsh DM
    5. Shankar GM
    6. Selkoe D

    (2009) Soluble oligomers of amyloid beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake

    Neuron 62:788–801.

    https://doi.org/10.1016/j.neuron.2009.05.012

    • Google Scholar
39. 1. Li H
    2. Wang Z
    3. Wang B
    4. Guo Q
    5. Dolios G
    6. Tabuchi K
    7. Hammer RE
    8. Südhof TC
    9. Wang R
    10. Zheng H

    (2010) Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis

    The Journal of Biological Chemistry 285:30598–30605.

    https://doi.org/10.1074/jbc.M110.137729

    • Google Scholar
40. 1. Liu Q
    2. Zerbinatti CV
    3. Zhang J
    4. Hoe HS
    5. Wang B
    6. Cole SL
    7. Herz J
    8. Muglia L
    9. Bu G

    (2007) Amyloid precursor protein regulates brain apolipoprotein e and cholesterol metabolism through lipoprotein receptor LRP1

    Neuron 56:66–78.

    https://doi.org/10.1016/j.neuron.2007.08.008

    • Google Scholar
41. 1. Lu DC
    2. Rabizadeh S
    3. Chandra S
    4. Shayya RF
    5. Ellerby LM
    6. Ye X
    7. Salvesen GS
    8. Koo EH
    9. Bredesen DE

    (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor

    Nature Medicine 6:397–404.

    https://doi.org/10.1038/74656

    • Google Scholar
42. 1. Lundgren JL
    2. Ahmed S
    3. Schedin-Weiss S
    4. Gouras GK
    5. Winblad B
    6. Tjernberg LO
    7. Frykman S

    (2015) ADAM10 and BACE1 are localized to synaptic vesicles

    Journal of Neurochemistry 135:.

    https://doi.org/10.1111/jnc.13287

    • Google Scholar
43. 1. Madeira A
    2. Pommet JM
    3. Prochiantz A
    4. Allinquant B

    (2005) SET protein (TAF1beta, I2PP2A) is involved in neuronal apoptosis induced by an amyloid precursor protein cytoplasmic subdomain

    FASEB Journal 19:1905–1907.

    https://doi.org/10.1096/fj.05-3839fje

    • Google Scholar
44. 1. Marcello E
    2. Epis R
    3. Saraceno C
    4. Di Luca M

    (2012) Synaptic dysfunction in alzheimer's disease

    Advances in Experimental Medicine and Biology 970:573–601.

    https://doi.org/10.1007/978-3-7091-0932-8_25

    • Google Scholar
45. 1. Matsuda S
    2. Giliberto L
    3. Matsuda Y
    4. Davies P
    5. McGowan E
    6. Pickford F
    7. Ghiso J
    8. Frangione B
    9. D'Adamio L

    (2005) The familial dementia BRI2 gene binds the alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production

    The Journal of Biological Chemistry 280:28912–28916.

    https://doi.org/10.1074/jbc.C500217200

    • Google Scholar
46. 1. Matsuda S
    2. Giliberto L
    3. Matsuda Y
    4. McGowan EM
    5. D'Adamio L

    (2008) BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate

    The Journal of Neuroscience 28:8668–8676.

    https://doi.org/10.1523/JNEUROSCI.2094-08.2008

    • Google Scholar
47. 1. Matsuda S
    2. Matsuda Y
    3. D'Adamio L

    (2009) BRI3 inhibits amyloid precursor protein processing in a mechanistically distinct manner from its homologue dementia gene BRI2

    The Journal of Biological Chemistry 284:15815–15825.

    https://doi.org/10.1074/jbc.M109.006403

    • Google Scholar
48. 1. McMahon HT
    2. Boucrot E

    (2011) Molecular mechanism and physiological functions of clathrin-mediated endocytosis

    Nature Reviews Molecular Cell Biology 12:517–533.

    https://doi.org/10.1038/nrm3151

    • Google Scholar
49. 1. Milosch N
    2. Tanriöver G
    3. Kundu A
    4. Rami A
    5. François JC
    6. Baumkötter F
    7. Weyer SW
    8. Samanta A
    9. Jäschke A
    10. Brod F
    11. Buchholz CJ
    12. Kins S
    13. Behl C
    14. Müller UC
    15. Kögel D

    (2014) Holo-APP and g-protein-mediated signaling are required for sAPPalpha-induced activation of the akt survival pathway

    Cell Death & Disease 5:e1391.

    https://doi.org/10.1038/cddis.2014.352

    • Google Scholar
50. 1. Mota SI
    2. Ferreira IL
    3. Rego AC

    (2014) Dysfunctional synapse in alzheimer's disease - a focus on NMDA receptors

    Neuropharmacology 76 Pt A:16–26.

    https://doi.org/10.1016/j.neuropharm.2013.08.013

    • Google Scholar
51. 1. Mucke L
    2. Selkoe DJ

    (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction

    Cold Spring Harbor Perspectives in Medicine 2:a006338.

    https://doi.org/10.1101/cshperspect.a006338

    • Google Scholar
52. 1. Müller UC
    2. Zheng H

    (2012) Physiological functions of APP family proteins

    Cold Spring Harbor Perspectives in Medicine 2:a006288.

    https://doi.org/10.1101/cshperspect.a006288

    • Google Scholar
53. 1. Neve RL
    2. Boyce FM
    3. McPhie DL
    4. Greenan J
    5. Oster-Granite ML

    (1996) Transgenic mice expressing APP-C100 in the brain

    Neurobiology of Aging 17:191–203.

    https://doi.org/10.1016/0197-4580(95)02074-8

    • Google Scholar
54. 1. Neve RL
    2. Robakis NK

    (1998) Alzheimer's disease: a re-examination of the amyloid hypothesis

    Trends in Neurosciences 21:15–19.

    https://doi.org/10.1016/S0166-2236(97)01168-5

    • Google Scholar
55. 1. Nikolaev A
    2. McLaughlin T
    3. O'Leary DD
    4. Tessier-Lavigne M

    (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

    Nature 457:981–989.

    https://doi.org/10.1038/nature07767

    • Google Scholar
56. 1. Norstrom EM
    2. Zhang C
    3. Tanzi R
    4. Sisodia SS

    (2010) Identification of NEEP21 as a beta-amyloid precursor protein-interacting protein in vivo that modulates amyloidogenic processing in vitro

    The Journal of Neuroscience 30:15677–15685.

    https://doi.org/10.1523/JNEUROSCI.4464-10.2010

    • Google Scholar
57. 1. O'Connell BC
    2. Harper JW

    (2007) Ubiquitin proteasome system (uPS): what can chromatin do for you?

    Current Opinion in Cell Biology 19:206–214.

    https://doi.org/10.1016/j.ceb.2007.02.014

    • Google Scholar
58. 1. Octave JN
    2. Pierrot N
    3. Ferao Santos S
    4. Nalivaeva NN
    5. Turner AJ

    (2013) From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein

    Journal of Neurochemistry 126:183–190.

    https://doi.org/10.1111/jnc.12239

    • Google Scholar
59. 1. Oster-Granite ML
    2. McPhie DL
    3. Greenan J
    4. Neve RL

    (1996)

    Age-dependent neuronal and synaptic degeneration in mice transgenic for the c terminus of the amyloid precursor protein

    The Journal of Neuroscience 16:6732–6741.

    • Google Scholar
60. 1. Parameshwaran K
    2. Dhanasekaran M
    3. Suppiramaniam V

    (2008) Amyloid beta peptides and glutamatergic synaptic dysregulation

    Experimental Neurology 210:7–13.

    https://doi.org/10.1016/j.expneurol.2007.10.008

    • Google Scholar
61. 1. Pardossi-Piquard R
    2. Petit A
    3. Kawarai T
    4. Sunyach C
    5. Alves da Costa C
    6. Vincent B
    7. Ring S
    8. D'Adamio L
    9. Shen J
    10. Müller U
    11. St George Hyslop P
    12. Checler F

    (2005) Presenilin-dependent transcriptional control of the abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP

    Neuron 46:541–554.

    https://doi.org/10.1016/j.neuron.2005.04.008

    • Google Scholar
62. 1. Passer B
    2. Pellegrini L
    3. Russo C
    4. Siegel RM
    5. Lenardo MJ
    6. Schettini G
    7. Bachmann M
    8. Tabaton M
    9. D'Adamio L

    (2000)

    Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of alzheimer's amyloid beta protein precursor

    Journal of Alzheimer's Disease : JAD 2:289–301.

    • Google Scholar
63. 1. Pellegrini L
    2. Passer BJ
    3. Tabaton M
    4. Ganjei JK
    5. D'Adamio L

    (1999) Alternative, non-secretase processing of alzheimer's -amyloid precursor protein during apoptosis by caspase-6 and -8

    Journal of Biological Chemistry 274:21011–21016.

    https://doi.org/10.1074/jbc.274.30.21011

    • Google Scholar
64. 1. Priller C
    2. Bauer T
    3. Mitteregger G
    4. Krebs B
    5. Kretzschmar HA
    6. Herms J

    (2006) Synapse formation and function is modulated by the amyloid precursor protein

    The Journal of Neuroscience 26:7212–7221.

    https://doi.org/10.1523/JNEUROSCI.1450-06.2006

    • Google Scholar
65. 1. Puzzo D
    2. Privitera L
    3. Leznik E
    4. Fà M
    5. Staniszewski A
    6. Palmeri A
    7. Arancio O

    (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus

    The Journal of Neuroscience 28:14537–14545.

    https://doi.org/10.1523/JNEUROSCI.2692-08.2008

    • Google Scholar
66. 1. Puzzo D
    2. Arancio O

    (2013) Amyloid-beta peptide: dr. jekyll or mr. hyde?

    Journal of Alzheimer's Disease 33:S111–S120.

    https://doi.org/10.3233/JAD-2012-129033

    • Google Scholar
67. 1. Randall AD
    2. Witton J
    3. Booth C
    4. Hynes-Allen A
    5. Brown JT

    (2010) The functional neurophysiology of the amyloid precursor protein (aPP) processing pathway

    Neuropharmacology 59:243–267.

    https://doi.org/10.1016/j.neuropharm.2010.02.011

    • Google Scholar
68. 1. Rizzoli SO

    (2014) Synaptic vesicle recycling: steps and principles

    The EMBO Journal 33:788–822.

    https://doi.org/10.1002/embj.201386357

    • Google Scholar
69. 1. Roberson ED
    2. Halabisky B
    3. Yoo JW
    4. Yao J
    5. Chin J
    6. Yan F
    7. Wu T
    8. Hamto P
    9. Devidze N
    10. Yu GQ
    11. Palop JJ
    12. Noebels JL
    13. Mucke L

    (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of alzheimer's disease

    The Journal of Neuroscience 31:700–711.

    https://doi.org/10.1523/JNEUROSCI.4152-10.2011

    • Google Scholar
70. 1. Royle SJ
    2. Lagnado L

    (2010) Clathrin-mediated endocytosis at the synaptic terminal: bridging the gap between physiology and molecules

    Traffic 11:1489–1497.

    https://doi.org/10.1111/j.1600-0854.2010.01104.x

    • Google Scholar
71. 1. Scheinfeld MH
    2. Ghersi E
    3. Laky K
    4. Fowlkes BJ
    5. D'Adamio L

    (2002) Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription

    The Journal of Biological Chemistry 277:44195–44201.

    https://doi.org/10.1074/jbc.M208110200

    • Google Scholar
72. 1. Scheinfeld MH
    2. Matsuda S
    3. D'Adamio L

    (2003) JNK-interacting protein-1 promotes transcription of a beta protein precursor but not a beta precursor-like proteins, mechanistically different than Fe65

    Proceedings of the National Academy of Sciences of the United States of America 100:1729–1734.

    https://doi.org/10.1073/pnas.0437908100

    • Google Scholar
73. 1. Selkoe D
    2. Kopan R

    (2003) Notch and presenilin: regulated intramembrane proteolysis links development and degeneration

    Annual Review of Neuroscience 26:565–597.

    https://doi.org/10.1146/annurev.neuro.26.041002.131334

    • Google Scholar
74. 1. Shankar GM
    2. Bloodgood BL
    3. Townsend M
    4. Walsh DM
    5. Selkoe DJ
    6. Sabatini BL

    (2007) Natural oligomers of the alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway

    The Journal of Neuroscience 27:2866–2875.

    https://doi.org/10.1523/JNEUROSCI.4970-06.2007

    • Google Scholar
75. 1. Sisodia SS
    2. St George-Hyslop PH

    (2002) Gamma-secretase, notch, abeta and alzheimer's disease: where do the presenilins fit in?

    Nature Reviews. Neuroscience 3:281–290.

    https://doi.org/10.1038/nrn785

    • Google Scholar
76. 1. Sivanesan S
    2. Tan A
    3. Rajadas J

    (2013) Pathogenesis of abeta oligomers in synaptic failure

    Current Alzheimer Research 10:316–323.

    https://doi.org/10.2174/1567205011310030011

    • Google Scholar
77. 1. Südhof TC
    2. Rizo J

    (2011) Synaptic vesicle exocytosis

    Cold Spring Harbor Perspectives in Biology 3:.

    https://doi.org/10.1101/cshperspect.a005637

    • Google Scholar
78. 1. Südhof TC

    (2012) The presynaptic active zone

    Neuron 75:11–25.

    https://doi.org/10.1016/j.neuron.2012.06.012

    • Google Scholar
79. 1. Südhof TC

    (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle

    Neuron 80:675–690.

    https://doi.org/10.1016/j.neuron.2013.10.022

    • Google Scholar
80. 1. Talani G
    2. Biggio G
    3. Sanna E

    (2011) Enhanced sensitivity to ethanol-induced inhibition of LTP in CA1 pyramidal neurons of socially isolated C57BL/6J mice: role of neurosteroids

    Frontiers in Endocrinology 2:56.

    https://doi.org/10.3389/fendo.2011.00056

    • Google Scholar
81. 1. Tamayev R
    2. Akpan N
    3. Arancio O
    4. Troy CM
    5. D'Adamio L

    (2012a) Caspase-9 mediates synaptic plasticity and memory deficits of danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection

    Molecular Neurodegeneration 7:60.

    https://doi.org/10.1186/1750-1326-7-60

    • Google Scholar
82. 1. Tamayev R
    2. D'Adamio L

    (2012b) Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of danish dementia

    Molecular Neurodegeneration 7:19.

    https://doi.org/10.1186/1750-1326-7-19

    • Google Scholar
83. 1. Tamayev R
    2. Matsuda S
    3. Arancio O
    4. D'Adamio L

    (2012c) Beta- but not gamma-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

    EMBO Molecular Medicine 4:171–179.

    https://doi.org/10.1002/emmm.201100195

    • Google Scholar
84. 1. Tanzi RE

    (2012) The genetics of alzheimer disease

    Cold Spring Harbor Perspectives in Medicine 2:.

    https://doi.org/10.1101/cshperspect.a006296

    • Google Scholar
85. 1. Turner PR
    2. O’Connor K
    3. Tate WP
    4. Abraham WC

    (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory

    Progress in Neurobiology 70:1–32.

    https://doi.org/10.1016/S0301-0082(03)00089-3

    • Google Scholar
86. 1. Um JW
    2. Nygaard HB
    3. Heiss JK
    4. Kostylev MA
    5. Stagi M
    6. Vortmeyer A
    7. Wisniewski T
    8. Gunther EC
    9. Strittmatter SM

    (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates fyn to impair neurons

    Nature Neuroscience 15:1227–1235.

    https://doi.org/10.1038/nn.3178

    • Google Scholar
87. 1. Vassar R
    2. Bennett BD
    3. Babu-Khan S
    4. Kahn S
    5. Mendiaz EA
    6. Denis P
    7. Teplow DB
    8. Ross S
    9. Amarante P
    10. Loeloff R
    11. Luo Y
    12. Fisher S
    13. Fuller J
    14. Edenson S
    15. Lile J
    16. Jarosinski MA
    17. Biere AL
    18. Curran E
    19. Burgess T
    20. Louis JC
    21. Collins F
    22. Treanor J
    23. Rogers G
    24. Citron M

    (1999) Beta-secretase cleavage of alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE

    Science 286:735–741.

    https://doi.org/10.1126/science.286.5440.735

    • Google Scholar
88. 1. Venkitaramani DV
    2. Chin J
    3. Netzer WJ
    4. Gouras GK
    5. Lesne S
    6. Malinow R
    7. Lombroso PJ

    (2007) Beta-amyloid modulation of synaptic transmission and plasticity

    The Journal of Neuroscience 27:11832–11837.

    https://doi.org/10.1523/JNEUROSCI.3478-07.2007

    • Google Scholar
89. 1. Vidal R
    2. Frangione B
    3. Rostagno A
    4. Mead S
    5. Révész T
    6. Plant G
    7. Ghiso J

    (1999) A stop-codon mutation in the BRI gene associated with familial british dementia

    Nature 399:776–781.

    https://doi.org/10.1038/21637

    • Google Scholar
90. 1. Vidal R
    2. Revesz T
    3. Rostagno A
    4. Kim E
    5. Holton JL
    6. Bek T
    7. Bojsen-Møller M
    8. Braendgaard H
    9. Plant G
    10. Ghiso J
    11. Frangione B

    (2000) A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a danish kindred

    Proceedings of the National Academy of Sciences of the United States of America 97:4920–4925.

    https://doi.org/10.1073/pnas.080076097

    • Google Scholar
91. 1. von Koch CS
    2. Zheng H
    3. Chen H
    4. Trumbauer M
    5. Thinakaran G
    6. van der Ploeg LHT
    7. Price DL
    8. Sisodia SS

    (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice

    Neurobiology of Aging 18:661–669.

    https://doi.org/10.1016/S0197-4580(97)00151-6

    • Google Scholar
92. 1. von Rotz RC
    2. Kohli BM
    3. Bosset J
    4. Meier M
    5. Suzuki T
    6. Nitsch RM
    7. Konietzko U

    (2004) The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

    Journal of Cell Science 117:4435–4448.

    https://doi.org/10.1242/jcs.01323

    • Google Scholar
93. 1. Wang P
    2. Yang G
    3. Mosier DR
    4. Chang P
    5. Zaidi T
    6. Gong YD
    7. Zhao NM
    8. Dominguez B
    9. Lee KF
    10. Gan WB
    11. Zheng H

    (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (aPP) and APP-like protein 2

    The Journal of Neuroscience 25:1219–1225.

    https://doi.org/10.1523/JNEUROSCI.4660-04.2005

    • Google Scholar
94. 1. Watanabe T
    2. Sukegawa J
    3. Sukegawa I
    4. Tomita S
    5. Iijima Ko-ichi
    6. Oguchi S
    7. Suzuki T
    8. Nairn AC
    9. Greengard P

    (1999) A 127-kDa protein (uV-DDB) binds to the cytoplasmic domain of the alzheimer's amyloid precursor protein

    Journal of Neurochemistry 72:549–556.

    https://doi.org/10.1046/j.1471-4159.1999.0720549.x

    • Google Scholar
95. 1. Weidemann A
    2. Paliga K
    3. Durrwang U
    4. Reinhard FBM
    5. Schuckert O
    6. Evin G
    7. Masters CL

    (1999) Proteolytic processing of the alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases

    Journal of Biological Chemistry 274:5823–5829.

    https://doi.org/10.1074/jbc.274.9.5823

    • Google Scholar
96. 1. Wilhelm BG
    2. Mandad S
    3. Truckenbrodt S
    4. Kröhnert K
    5. Schäfer C
    6. Rammner B
    7. Koo SJ
    8. Claßen GA
    9. Krauss M
    10. Haucke V
    11. Urlaub H
    12. Rizzoli SO

    (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins

    Science 344:1023–1028.

    https://doi.org/10.1126/science.1252884

    • Google Scholar
97. 1. Willem M
    2. Tahirovic S
    3. Busche MA
    4. Ovsepian SV
    5. Chafai M
    6. Kootar S
    7. Hornburg D
    8. Evans LD
    9. Moore S
    10. Daria A
    11. Hampel H
    12. Müller V
    13. Giudici C
    14. Nuscher B
    15. Wenninger-Weinzierl A
    16. Kremmer E
    17. Heneka MT
    18. Thal DR
    19. Giedraitis V
    20. Lannfelt L
    21. Müller U
    22. Livesey FJ
    23. Meissner F
    24. Herms J
    25. Konnerth A
    26. Marie H
    27. Haass C

    (2015) η-secretase processing of APP inhibits neuronal activity in the hippocampus

    Nature 526:443–447.

    https://doi.org/10.1038/nature14864

    • Google Scholar
98. 1. Wu B
    2. Yamaguchi H
    3. Lai FA
    4. Shen J

    (2013) Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons

    Proceedings of the National Academy of Sciences of the United States of America 110:15091–15096.

    https://doi.org/10.1073/pnas.1304171110

    • Google Scholar
99. 1. Xia D
    2. Watanabe H
    3. Wu B
    4. Lee SH
    5. Li Y
    6. Tsvetkov E
    7. Bolshakov VY
    8. Shen J
    9. Kelleher RJ

    (2015) Presenilin-1 knockin mice reveal loss-of-function mechanism for familial alzheimer's disease

    Neuron 85:967–981.

    https://doi.org/10.1016/j.neuron.2015.02.010

    • Google Scholar
100. 1. Xu J
     2. Pang ZP
     3. Shin OH
     4. Südhof TC

     (2009) Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release

     Nature Neuroscience 12:759–766.

     https://doi.org/10.1038/nn.2320

     • Google Scholar
101. 1. Yang G
     2. Gong YD
     3. Gong K
     4. Jiang WL
     5. Kwon E
     6. Wang P
     7. Zheng H
     8. Zhang XF
     9. Gan WB
     10. Zhao NM

     (2005) Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (aPP) and APP-like protein 2

     Neuroscience Letters 384:66–71.

     https://doi.org/10.1016/j.neulet.2005.04.040

     • Google Scholar
102. 1. Zhang C
     2. Wu B
     3. Beglopoulos V
     4. Wines-Samuelson M
     5. Zhang D
     6. Dragatsis I
     7. Südhof TC
     8. Shen J

     (2009) Presenilins are essential for regulating neurotransmitter release

     Nature 460:632–636.

     https://doi.org/10.1038/nature08177

     • Google Scholar
103. 1. Zucker RS
     2. Regehr WG

     (2002) Short-term synaptic plasticity

     Annual Review of Physiology 64:355–405.

     https://doi.org/10.1146/annurev.physiol.64.092501.114547

     • Google Scholar

Author details

1. Tomas Fanutza

   Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

   Contribution

   TF, Prepared samples for electrophysiology recordings. Performed the electrophysiology recordings. Analyzed and interpreted the electrophysiology recordings, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Dolores Del Prete

   Competing interests

   The authors declare that no competing interests exist.

2. Dolores Del Prete

   Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

   Contribution

   DDP, Performed biochemical experiments. Generated the KO mice. Performed IF experiments. Prepared samples for electrophysiology recordings. Analyzed and interpreted the electrophysiology recordings, Acquisition of data, Analysis and interpretation of data

   Contributed equally with

   Tomas Fanutza

   Competing interests

   The authors declare that no competing interests exist.

3. Michael J Ford

   MS Bioworks, LLC, Ann Arbor, United States

   Contribution

   MJF, Performed the proteomic analysis

   Competing interests

   The authors declare that no competing interests exist.

4. Pablo E Castillo

   Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

   Contribution

   PEC, Contributed to the analysis, interpretation and planning of electrophysiology experiments. Contributed to writing the paper. Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   pablo.castillo@einstein.yu.edu

   Competing interests

   The authors declare that no competing interests exist.

5. Luciano D’Adamio

   Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, United States

   Contribution

   LD’A, Designed experiments. Performed biochemical experiments. Generated the KO mice. Analyzed and interpreted the data. Wrote the manuscript; Conception and design, Acquisition of data, Analysis and interpretation of data; Drafting or revising the article

   For correspondence

   luciano.dadamio@einstein.yu.edu

   Competing interests

   The authors declare that no competing interests exist.

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