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.

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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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