NPTX2 and cognitive dysfunction in Alzheimer’s Disease
- Johns Hopkins University School of Medicine, United States
- Eunice Kennedy-Shriver National Institute of Child Health and Human Development, United States
- National Institute on Aging, Intramural Research Program, United States
- University of California San Diego Medical Center, United States
- University of California San Diego, United States
- Institute for Basic Research, United States
- Columbia University, United States
Figures
Figure 1 with 2 supplements
NPTX2 levels are reduced in human postmortem AD brain and DS brain, but not in ASYMAD brain.
(A,B,D and E) Representative western blot images (A) and quantification of NPTX2 (B), NPTX1 (D) and NPTXR (E) normalized to PSD95 in the frontopolar cortex (FPC), precuneus (PCU), occipital gyrus …
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Figure 1—source data 1
Clinical and histopathological information of ASYMAD and AD individuals for brain analysis.
- https://doi.org/10.7554/eLife.23798.003
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Figure 1—source data 2
Information of individuals with Down syndrome for brain analysis.
- https://doi.org/10.7554/eLife.23798.004
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Figure 1—source data 3
Information of individuals with Down syndrome and Alzheimer’s disease for brain analysis.
- https://doi.org/10.7554/eLife.23798.005
Figure 1—figure supplement 1
Immediate early gene expression in human postmortem AD brain.
(A) NPTX2 levels are reduced in human postmortem AD brain. Quantification of NPTX2, NPTX1 and NPTXR levels in Figure 1A with actin as reference protein. NPTX2 is down-regulated in all assayed brain …
Figure 1—figure supplement 2
NPTX2 levels are reduced in human postmortem DS-AD brain.
(A) Western blot assays show NPTX2 down-regulation in superior frontal gyrus (SFG) of individuals with Down syndrome and Alzheimer’s disease (DS-AD). Control, n = 8; DS-AD, n = 12. (B) Nptx2 mRNA is …
Figure 2 with 2 supplements
miRNAs dysregulation and NPTX2 down-regulation in AD brains.
(A) Nptx2 pre-mRNA levels are identical in frontopolar cortex (FPC) of AD subjects and control. Control, n = 9; AD, n = 16. (B) microRNAs predicted to bind with Nptx2 3’UTR by TargetScan. (C) Taqman …
Figure 2—figure supplement 1
Methylation of Nptx2 promoter in human brain.
(A) Representative pyrosequencing traces show high methylation of Nptx2 promoter in pancreatic cell line AsPC1 cells, and low methylation in human brain. (B) Nptx2 promoter methylation in brains is …
Figure 2—figure supplement 2
Nptx2 mRNA is targeted by miRNAs that are upregulated in AD brain.
(A) miR-1271 up-regulation correlates with reduced Nptx2 mRNA. Control, n = 9; AD, n = 16. Pearson correlation coefficient analysis was performed. (B,C) Assays of Nptx2 mRNA and miRNA in AD …
Figure 3 with 2 supplements
Circuit Rhythmicity and GluA4 expression are disrupted in hAPP/Nptx2-/- mice.
(A–D) Example extracellular field potentials (i) with hatched area shown on an expanded time base (ii) for WT (A), Nptx2-/- (B), hAPP (C), and hAPP/Nptx2-/- (D) mice. For hAPP/Nptx2-/- trace, grey …
Figure 3—figure supplement 1
NPTX2 expression in amyloidosis mouse model.
Western blot assays show no significant change of NPTX2 expression in 6 month-old male APPswe/PS1∆E9 (hAPP) mouse brain when compared with wildtype (WT). n = 3. Two-tailed t test was performed. Data …
Figure 3—figure supplement 2
Spontaneous sharp-wave ripples (SWRs) occur more frequently in hAPP/Nptx2-/- mice.
(A–D) Example extracellular field recordings showing SWRs in unfiltered traces (i), with the boxed area filtered (100 to 250 Hz) to show an individual SWR (ii) and the corresponding wavelet …
Figure 4
GluA4 levels are reduced in human postmortem AD brain.
(A) Immunostaining of GluA4 demonstrates GluA4 is enriched on PV-IN in human cortex. Data were collected from four cases including occipital gyrus and parietal gyrus. (B and C) Representative …
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Figure 4—source data 1
Information of young healthy controls and aged healthy controls for brain analysis.
- https://doi.org/10.7554/eLife.23798.015
Figure 5 with 5 supplements
NPTX levels are reduced in CSF from individuals with clinically diagnosed AD.
(A,B) Western blot assays of NPTX2, NPTX1 and NPTXR in lumbar cerebrospinal fluid (CSF) from age-matched controls and patients with clinically diagnosed AD. AD patients show reduced NPTX2, NPTX1 and …
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Figure 5—source data 1
Summary of human CSF analysis in Alzheimer’s disease (first cohort).
- https://doi.org/10.7554/eLife.23798.017
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Figure 5—source data 2
Summary of human CSF analysis in Alzheimer’s disease (second cohort).
- https://doi.org/10.7554/eLife.23798.018
Figure 5—figure supplement 1
Reduction of NPTXR levels in lumbar cerebrospinal fluid (CSF) from individuals with AD.
(A) Representative western blot images show three major bands with human CSF samples by NPTXR antibody. (B) Patients with clinically diagnosed AD have reduced NPTXR levels in CSF compared with …
Figure 5—figure supplement 2
Detection of NPTX in human CSF.
(A) NPTX2 and NPTX1 are detected in lumbar CSF of human subjects as a high molecular weight complex that is resolved into individual NPTXs with reducing reagent on SDS-PAGE. Arrows indicate monomer …
Figure 5—figure supplement 3
Development of NPTX2 ELISA assay.
(A,B) Generation of mouse monoclonal NPTX2 antibody (A) and purification of NPTX2 protein (B) for ELISA assay. Western blots using mouse NPTX2 monoclonal antibody show a 50 kDa band in WT brain …
Figure 5—figure supplement 4
Reduction of NPTX levels in second set of CSF from individuals with AD.
Representative western blot images and quantification of NPTX2, NPTX1 and NPTXR in second set of lumbar CSF from patients with clinically diagnosed AD. AD patients show reduced NPTX2, NPTX1 and …
Figure 5—figure supplement 5
Positive correlation of NPTXs with CSF tau and p-tau.
(A–C) CSF NPTX2 levels correlate with CSF Tau (B) and p-Tau (C), but not with CSF Aβ42 (A) in AD patients. n = 49–51. Pearson correlation coefficient analysis was performed. (D–F) CSF NPTX1 levels …
Figure 6
NPTX2 expression correlates with cognitive performance and measures of hippocampal volume.
(A) NPTX2 expression in CSF correlates with cognitive function assayed by DRS in AD group. n = 30. p=0.0093 by Pearson correlation coefficient analysis. DRS: dementia rating scale. (B–D) No …
Tables
Table 1
Correlation analysis of CSF biomarkers with hippocampal size and clinical cognitive tests in AD subjects from second cohort.
| Vs CSF NPTX2 | Vs CSF aβ42 | Vs CSF tau | Vs CSF p-Tau | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | Pearson r | p value | n | Pearson r | p value | n | Pearson r | p value | n | Pearson r | p value | |
| Average Hippocampal Occupancy | 25 | 0.483 | 0.015 | 25 | 0.189 | 0.367 | 24 | −0.083 | 0.701 | 24 | 0.360 | 0.084 |
| Dementia Rating Scale | 30 | 0.467 | 0.009 | 28 | 0.225 | 0.249 | 27 | −0.137 | 0.497 | 27 | 0.296 | 0.134 |
| Digit Symbol Substitution | 24 | 0.446 | 0.029 | 23 | 0.127 | 0.565 | 22 | 0.095 | 0.673 | 22 | 0.043 | 0.849 |
| Boston Naming Test | 28 | 0.208 | 0.288 | 27 | 0.098 | 0.628 | 26 | −0.084 | 0.682 | 26 | 0.288 | 0.154 |
| Phonemic Verbal Fluency Test | 28 | 0.200 | 0.308 | 27 | −0.079 | 0.694 | 26 | −0.207 | 0.310 | 26 | 0.133 | 0.519 |
| Semantic Verbal Fluency Test | 28 | 0.385 | 0.043 | 27 | 0.396 | 0.041 | 26 | 0.121 | 0.557 | 26 | 0.036 | 0.863 |
| Wisconsin Card Sorting Task_categories achieved | 22 | 0.445 | 0.038 | 21 | 0.046 | 0.842 | 20 | −0.179 | 0.453 | 20 | −0.057 | 0.812 |
| Wisconsin Card Sorting Task_perseverative errors | 22 | −0.324 | 0.142 | 21 | 0.147 | 0.526 | 20 | 0.013 | 0.956 | 20 | −0.153 | 0.519 |
| Visual Reproduction Test_immediate recall | 24 | 0.432 | 0.035 | 23 | 0.149 | 0.497 | 22 | 0.325 | 0.140 | 22 | 0.292 | 0.187 |
| Visual Reproduction Test_delayed recall | 24 | 0.345 | 0.099 | 23 | 0.123 | 0.577 | 22 | −0.392 | 0.072 | 22 | −0.013 | 0.955 |
| Block Design | 28 | 0.446 | 0.017 | 27 | 0.082 | 0.683 | 26 | −0.111 | 0.590 | 26 | 0.004 | 0.984 |
| Clock Drawing_command | 28 | 0.337 | 0.079 | 27 | 0.040 | 0.845 | 26 | −0.119 | 0.563 | 26 | 0.087 | 0.673 |
| Clock Drawing_copy | 28 | 0.011 | 0.955 | 27 | 0.106 | 0.600 | 26 | −0.246 | 0.225 | 26 | 0.161 | 0.434 |
| California Verbal Learning Test_list B recall | 20 | 0.520 | 0.019 | 20 | 0.668 | 0.001 | 19 | 0.200 | 0.411 | 19 | −0.124 | 0.613 |
| California Verbal Learning Test_recognition | 20 | 0.109 | 0.647 | 20 | −0.096 | 0.687 | 19 | 0.046 | 0.851 | 19 | 0.221 | 0.364 |
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Significant correlations (p < 0.05) are highlighted in yellow.
