Faculty, Staff and Student Publications

Language

English

Publication Date

3-31-2023

Journal

Acta Neuropathologica Communications

DOI

10.1186/s40478-023-01552-7

PMID

37004141

PMCID

PMC10067183

PubMedCentral® Posted Date

3-31-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.

Keywords

Humans, Alzheimer Disease, Synapses, Presynaptic Terminals, Mitochondria, Brain, Alzheimer disease, Mitochondria, Synapse, Dense core vesicle, Dendritic spine, Synaptic vesicles

Published Open-Access

yes

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