The hypothesis proposes that stabilizing hippocampal CA3-CA1 synaptic function through DHHC2-mediated PSD95 palmitoylation can rescue synaptic transmission in Alzheimer's disease (AD), with BDNF signaling as a key downstream effector of this structural stabilization.
DHHC2 palmitoyltransferase catalyzes reversible palmitoylation of PSD95 at cysteine residues 3 and 5, promoting membrane association and preventing degradation by the ubiquitin-proteasome system. In AD, amyloid-β oligomers disrupt this process by sequestering Rab8a, a small GTPase required for DHHC2 membrane trafficking and localization to postsynaptic sites. This disruption leads to hypopalmitoylation of PSD95, causing its dissociation from the postsynaptic membrane and subsequent proteasomal degradation, which destabilizes AMPA and NMDA receptor clustering and impairs synaptic transmission. BDNF signaling becomes compromised downstream as PSD95 loss disrupts TrkB receptor complex assembly and associated signaling cascades essential for synaptic plasticity and neuronal survival [1].
Curated pathway from expert analysis
graph TD
A["Amyloid-beta<br/>Oligomers"] -->|"Sequestration"| B["Rab8a Small<br/>GTPase"]
B -->|"Impaired trafficking"| C["DHHC2<br/>Palmitoyltransferase"]
C -->|"Reduced membrane<br/>localization"| D["PSD95<br/>Hypopalmitoylation"]
E["Normal DHHC2<br/>Activity"] -->|"Palmitoylation at<br/>Cys3 and Cys5"| F["PSD95 Membrane<br/>Association"]
F -->|"Scaffold stability"| G["AMPA Receptor<br/>Clustering"]
F -->|"Scaffold stability"| H["NMDA Receptor<br/>Clustering"]
D -->|"Loss of membrane<br/>association"| I["PSD95 Dissociation<br/>from Membrane"]
I -->|"Targeting for<br/>degradation"| J["Ubiquitin-Proteasome<br/>System Activation"]
J -->|"Protein degradation"| K["PSD95 Loss"]
K -->|"Disrupted receptor<br/>clustering"| L["Synaptic Transmission<br/>Impairment"]
K -->|"Loss of scaffold<br/>integrity"| M["TrkB Receptor<br/>Complex Disruption"]
M -->|"Impaired signaling"| N["BDNF Pathway<br/>Dysfunction"]
N -->|"Reduced neurotrophic<br/>support"| O["Synaptic Plasticity<br/>Deficits"]
O -->|"Functional decline"| P["CA3-CA1 Synaptic<br/>Failure"]
P -->|"Circuit dysfunction"| Q["Hippocampal Memory<br/>Impairment"]
L -->|"Excitotoxicity"| R["Neuronal Survival<br/>Compromise"]
classDef normal fill:#4fc3f7,stroke:#2196f3,color:#0d0d1a
classDef therapeutic fill:#81c784,stroke:#4caf50,color:#0d0d1a
classDef pathology fill:#ef5350,stroke:#f44336,color:#0d0d1a
classDef outcome fill:#ffd54f,stroke:#ff9800,color:#0d0d1a
classDef molecular fill:#ce93d8,stroke:#9c27b0,color:#0d0d1a
class E,F,C normal
class A,D,I,J,K pathology
class N,O,P,Q,R outcome
class B,G,H,L,M molecularNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for BDNF from GTEx v10.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for BDNF.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Selective noradrenaline depletion in APP/PS1 transgenic mice will exacerbate synaptic deficits, demonstrating that interneuron dysfunction is secondary to broader neurotransmitter system collapse rath | Greater magnitude of synaptic impairment (measured by reduced EPSP slope, decreased spine density, and impaired LTP) in APP/PS1 mice with selective noradrenalin | — no observation — | open | 0.50 |
| Selective modulation of GluN2B-containing NMDA receptors will restore thalamocortical oscillatory coupling in neurodegeneration models, with altered GluN2B expression correlating with circuit dysfunct | Administration of GluN2B-selective antagonist (if unexpected enhancement needed) or ifenprodil/nethiergin antagonizing excessive GluN2B activity will normalize | — no observation — | pending | 0.45 |
| NMDA receptor antagonism will prevent synaptic depression but NOT prevent spine loss in Aβ models, distinguishing between NMDAR-dependent signaling cascades and structural Aβ toxicity | Memantine or D-AP5 treatment in Aβ-oligomer exposed hippocampal slices will preserve normal EPSP responses (preventing synaptic depression) while spine density | — no observation — | pending | 0.40 |
| Optogenetic activation of SST interneurons in Aβ-oligomer injected mice will selectively restore theta band oscillations to baseline levels, while optogenetic activation of PV interneurons will select | Measurable increase in theta (4-8 Hz) and gamma (30-100 Hz) oscillatory power specifically in hippocampal circuits of Aβ-treated mice following cell-type-specif | — no observation — | pending | 0.55 |