Dataset Information

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

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.

SUBMITTER: Wang W

PROVIDER: S-EPMC10067183 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

Wang Wenzhang W Zhao Fanpeng F Lu Yubing Y Siedlak Sandra L SL Fujioka Hisashi H Feng Hao H Perry George G Zhu Xiongwei X

Acta neuropathologica communications 20230331 1

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 ...[more]

PMID: 37004141

Similar Datasets

Project description:Lipid dyshomeostasis is associated with the most common form of dementia, Alzheimer's disease (AD). Substantial progress has been made in identifying positron emission tomography and cerebrospinal fluid biomarkers for AD, but they have limited use as front-line diagnostic tools. Extracellular vesicles (EVs) are released by all cells and contain a subset of their parental cell composition, including lipids. EVs are released from the brain into the periphery, providing a potential source of tissue and disease specific lipid biomarkers. However, the EV lipidome of the central nervous system is currently unknown and the potential of brain-derived EVs (BDEVs) to inform on lipid dyshomeostasis in AD remains unclear. The aim of this study was to reveal the lipid composition of BDEVs in human frontal cortex, and to determine whether BDEVs have an altered lipid profile in AD. Using semi-quantitative mass spectrometry, we describe the BDEV lipidome, covering four lipid categories, 17 lipid classes and 692 lipid molecules. BDEVs were enriched in glycerophosphoserine (PS) lipids, a characteristic of small EVs. Here we further report that BDEVs are enriched in ether-containing PS lipids, a finding that further establishes ether lipids as a feature of EVs. BDEVs in the AD frontal cortex offered improved detection of dysregulated lipids in AD over global lipid profiling of this brain region. AD BDEVs had significantly altered glycerophospholipid and sphingolipid levels, specifically increased plasmalogen glycerophosphoethanolamine and decreased polyunsaturated fatty acyl containing lipids, and altered amide-linked acyl chain content in sphingomyelin and ceramide lipids relative to CTL. The most prominent alteration was a two-fold decrease in lipid species containing anti-inflammatory/pro-resolving docosahexaenoic acid. The in-depth lipidome analysis provided in this study highlights the advantage of EVs over more complex tissues for improved detection of dysregulated lipids that may serve as potential biomarkers in the periphery.

Project description:BackgroundIdentifying effective strategies to prevent memory loss in AD has eluded researchers to date, and likely reflects insufficient understanding of early pathogenic mechanisms directly affecting memory encoding. As synaptic loss best correlates with memory loss in AD, refocusing efforts to identify factors driving synaptic impairments may provide the critical insight needed to advance the field. In this study, we reveal a previously undescribed cascade of events underlying pre and postsynaptic hippocampal signaling deficits linked to cognitive decline in AD. These profound alterations in synaptic plasticity, intracellular Ca2+ signaling, and network propagation are observed in 3-4 month old 3xTg-AD mice, an age which does not yet show overt histopathology or major behavioral deficits.MethodsIn this study, we examined hippocampal synaptic structure and function from the ultrastructural level to the network level using a range of techniques including electron microscopy (EM), patch clamp and field potential electrophysiology, synaptic immunolabeling, spine morphology analyses, 2-photon Ca2+ imaging, and voltage-sensitive dye-based imaging of hippocampal network function in 3-4 month old 3xTg-AD and age/background strain control mice.ResultsIn 3xTg-AD mice, short-term plasticity at the CA1-CA3 Schaffer collateral synapse is profoundly impaired; this has broader implications for setting long-term plasticity thresholds. Alterations in spontaneous vesicle release and paired-pulse facilitation implicated presynaptic signaling abnormalities, and EM analysis revealed a reduction in the ready-releasable and reserve pools of presynaptic vesicles in CA3 terminals; this is an entirely new finding in the field. Concurrently, increased synaptically-evoked Ca2+ in CA1 spines triggered by LTP-inducing tetani is further enhanced during PTP and E-LTP epochs, and is accompanied by impaired synaptic structure and spine morphology. Notably, vesicle stores, synaptic structure and short-term plasticity are restored by normalizing intracellular Ca2+ signaling in the AD mice.ConclusionsThese findings suggest the Ca2+ dyshomeostasis within synaptic compartments has an early and fundamental role in driving synaptic pathophysiology in early stages of AD, and may thus reflect a foundational disease feature driving later cognitive impairment. The overall significance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic vesicle stores, synaptic plasticity, and network propagation, which directly impact memory encoding.

Project description:BackgroundChronic brain hypoperfusion (CBH) is closely related to Alzheimer's disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear.MethodsIn the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1-43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO).ResultsCompared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1-43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2'-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3' untranslated region (3'UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats.ConclusionsOverexpression of miR-153 controls CBH-induced presynaptic vesicle release impairment by posttranscriptionally regulating the expression of four vesicle release-related proteins by targeting the 3'UTRs of the Stx1a, Snap25, Vamp2 and Syt1 genes. These findings identify a novel mechanism of presynaptic plasticity impairment during CBH, which may be a new drug target for prevention or treatment of AD and VaD. Video Abstract.

Dataset Information

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

Publications

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets