Dataset Information

Impaired presynaptic proteostasis in the initial stages of amyloid beta proteotoxicity

ABSTRACT: Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimers disease (AD); however, little is known about the early mechanisms that contribute to this accumulation. To objectively assess the impaired protein turnover at early stages of amyloid beta (Abeta) proteotoxicity, we used dynamic 15N metabolic labeling followed by proteomic analysis of amyloid precursor protein knock in mouse brains. At initial stages of Abeta accumulation the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV) associated proteins, have elevated levels, misfold in both a plaque dependent and independent manner, and interact with APP and Abeta. Concurrent with elevated levels of SV associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jeffrey N. Savas, PhD

PROVIDER: MSV000085004 | MassIVE | Mon Feb 24 17:36:00 GMT 2020

REPOSITORIES: MassIVE

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Publications

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Hark Timothy J TJ Rao Nalini R NR Castillon Charlotte C Basta Tamara T Smukowski Samuel S Bao Huan H Upadhyay Arun A Bomba-Warczak Ewa E Nomura Toshihiro T O'Toole Eileen T ET Morgan Garry P GP Ali Laith L Saito Takashi T Guillermier Christelle C Saido Takaomi C TC Steinhauser Matthew L ML Stowell Michael H B MHB Chapman Edwin R ER Contractor Anis A Savas Jeffrey N JN

Cell systems 20201215 2

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is ...[more]

PMID: 33326751

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Project description:Extracellular senile plaques of amyloid beta (Abeta) are a pathological hallmark in brain of patients with Alzheimer`s Disease (AD). Abeta is generated by the amyloidogenic processing of the amyloid precursor protein (APP). Concomitant to Abeta load, AD brain is characterized by an increase in protein level and activity of the angiotensin-converting enzyme (ACE). ACE inhibitors are a widely used class of drugs with established benefits for patients with cardiovascular disease. However, the role of ACE and ACE inhibition in the development of Abeta plaques and the process of AD-related neurodegeneration is not clear since ACE was reported to degrade Abeta. To investigate the effect of ACE inhibition on AD-related pathomechanisms, we used Tg2576 mice with neuron-specific expression of APPSwe as AD model. From 12 months of age, substantial Abeta plaque load accumulates in the hippocampus of Tg2576 mice as a brain region, which is highly vulnerable to AD-related neurodegeneration. The effect of central ACE inhibition was studied by treatment of 12 month-old Tg2576 mice for six months with the brain penetrating ACE inhibitor captopril. At an age of 18 months, hippocampal gene expression profiling was performed of captopril-treated Tg2576 mice relative to untreated 18 month-old Tg2576 controls with high Abeta plaque load. As an additional control, we used 12 month-old Tg2576 mice with low Abeta plaque load. Whole genome microarray gene expression profiling revealed gene expression changes induced by the brain-penetrating ACE inhibitor captopril, which could reflect the neuro-regenerative potential of central ACE inhibition. Microarray gene expression profiling was performed of hippocampi isolated from aged, 18 month-old Tg2576 (APPSwe-transgenic) AD mice with high Abeta plaque load relative to age-matched Tg2576 mice, which were treated for 6 months with the centrally active ACE inhibitor captopril. Another study group consisted of 12 month-old Tg2576 mice with low Abeta plaque load. In total, three study groups were analyzed, i.e. (i) 18 month-old untreated Tg2576 mice with high Abeta plaque load, (ii) age-matched Tg2576 mice treated for 6 months with the brain-penetrating ACE inhibitor captopril (20 mg/kg body weight/day in drinking water), and (iii) untreated 12 month-old Tg2576 mice with low Abeta plaque load reflecting the time point when captopril treatment was initiated. Two biological replicates were made of each group, and total hippocampal RNA of four mice was pooled for one gene chip.

Dataset Information

Impaired presynaptic proteostasis in the initial stages of amyloid beta proteotoxicity

Publications

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Similar Datasets

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