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A synapsin Ⅰ cleavage fragment contributes to synaptic dysfunction in Alzheimer's disease.

ABSTRACT: Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C-terminal synapsin Ⅰ (83-705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. Overexpression of AEP in the hippocampus of wild-type mice results in the production of the synapsin Ⅰ (83-705) fragment and induces synaptic dysfunction and cognitive deficits. Moreover, overexpression of the AEP-generated synapsin Ⅰ (83-705) fragment in the hippocampus of tau P301S transgenic mice and wild-type mice promotes synaptic dysfunction and cognitive deficits. These findings suggest a novel mechanism of synaptic dysfunction in AD.

SUBMITTER: Meng L

PROVIDER: S-EPMC9124304 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A synapsin Ⅰ cleavage fragment contributes to synaptic dysfunction in Alzheimer's disease.

Meng Lanxia L Zou Li L Xiong Min M Chen Jiehui J Zhang Xingyu X Yu Ting T Li Yiming Y Liu Congcong C Chen Guiqin G Wang Zhihao Z Ye Keqiang K Zhang Zhentao Z

Aging cell 20220420 5

Synaptic dysfunction is a key feature of Alzheimer's disease (AD). However, the molecular mechanisms underlying synaptic dysfunction remain unclear. Here, we show that synapsin Ⅰ, one of the most important synaptic proteins, is fragmented by the cysteine proteinase asparagine endopeptidase (AEP). AEP cleaves synapsin at N82 in the brains of AD patients and generates the C-terminal synapsin Ⅰ (83-705) fragment. This fragment is abnormally distributed in neurons and induces synaptic dysfunction. O ...[more]

PMID: 35443102

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Project description:Tau cleavage plays a crucial role in the onset and progression of Alzheimer's Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)-a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance-mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it's in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

Dataset Information

A synapsin Ⅰ cleavage fragment contributes to synaptic dysfunction in Alzheimer's disease.

Publications

A synapsin Ⅰ cleavage fragment contributes to synaptic dysfunction in Alzheimer's disease.

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