PSD-95 protects synapses from β-amyloid.
Kim Dore1, Zachary Carrico1, Stephanie Alfonso1
1Center for Neural Circuits and Behavior, Department of Neuroscience and Section for Neurobiology, Division of Biology, University of California, San Diego, San Diego, CA 92093, USA.
Cell Reports
|June 2, 2021
Summary
Increased PSD-95 protein protects synapses from beta-amyloid toxicity by stabilizing NMDA receptor interactions. This finding suggests targeting PSD-95 could be a therapeutic strategy for Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Beta-amyloid (Aβ) accumulation is a hallmark of Alzheimer's disease.
- Aβ impairs excitatory synapses through mechanisms involving NMDA receptor (NMDAR) function.
- The precise molecular pathways linking Aβ to synaptic dysfunction remain incompletely understood.
Purpose of the Study:
- To elucidate the role of the synaptic scaffolding protein PSD-95 in mediating Aβ-induced synaptic depression.
- To investigate how PSD-95 levels influence NMDAR function and synaptic integrity in the presence of Aβ.
Main Methods:
- Utilized electrophysiological recordings in brain tissue.
- Investigated protein-protein interactions involving NMDAR C-terminal domains (CTD) and protein phosphatase 1 (PP1).
- Examined the effects of altered PSD-95 levels (endogenous or overexpressed) and pharmacological inhibition of depalmitoylation.
Main Results:
- Increased PSD-95 levels were found to block the detrimental effects of Aβ on excitatory synapses.
- Aβ alters NMDAR CTD conformation and its interaction with PP1, leading to synaptic weakening.
- Elevated PSD-95 prevents these Aβ-induced molecular changes at the NMDAR, preserving synaptic function.
- Pharmacological inhibition of PSD-95 depalmitoylation increased synaptic PSD-95 and rescued Aβ-induced deficits.
Conclusions:
- Elevated synaptic PSD-95 confers protection against Aβ-induced synaptic toxicity.
- Low synaptic PSD-95 levels may indicate synapse vulnerability in Alzheimer's disease.
- Modulating PSD-95 levels, potentially via depalmitoylation inhibition, represents a promising therapeutic strategy for Alzheimer's disease.
Related Concept Videos
03:03Amyloid Fibrils
10.9K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
10.9K
03:03Amyloid Fibrils
6.0K
6.0K
01:22Alzheimer's Disease: Treatment
457
Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
457