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Label free -DDA nano-LC/MS/MS analysis of aggregates and total hippocampal proteome in an early AD mouse model following activation of chaperone-mediated autophagy

ABSTRACT: Neurons are postmitotic cells that are highly sensitive to proteotoxic insults and reliant on tight protein quality control. Several forms of autophagy co-exist in neurons to maintain proteostasis. Defective autophagic pathways are one of the key hallmarks of the aging and neurodegenerative brains. Chaperone-mediated autophagy (CMA) declines in neurons in aging and neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease. CMA loss in neurons leads to protein aggregation, neuronal hyperactivity, neurodegeneration, and cognitive decline, all reminiscent of brain again. Conversely, pharmacological enhancement of CMA reduces pathological tau and β-amyloid accumulation, mitigates neuronal hyperactivity and seizure susceptibility and ameliorates cognitive decline in multiple tauopathy mouse models. The molecular mechanism underlying the beneficial role of CMA activation in AD is largely unknow. Furthermore, neuronal hyperactivity has recently been proposed as an early hallmark of AD. However, the mechanisms underlying early neuronal hyperactivity in AD are also not fully understood. To investigate these molecular mechanisms, we performed quantitative proteomics in an AD mouse model in early disease following CMA activation. The study analyzed total as well as aggregating proteome in hippocampus of triple-transgenic (x3TG) AD mice (expressing APPSwe, PS2N141I, and hTauP301L) following CMA activation with CA77.1 from 4-6 months of age. 5-6 samples per group were analyzed. Following bottom-up analysis, the enrichment analysis – GO, Ingenuity pathway analysis (IPA) and String analysis identified several pathways predicting aberrant synaptogenesis and increased activation of excitatory synaptic proteome including glutamate receptor signaling which was corrected by CMA activation. CMA activation also reverted the enrichment of synaptic proteins in the aggregates in early AD hippocampus which may restore their aggregation-driven loss of function.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: ZOHAIB KHAN

LAB HEAD: Laura Santambrogio

PROVIDER: PXD057677 | Pride | 2025-09-04

REPOSITORIES: Pride

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			Action	DRS
	20240316_Lumos_OTIT_Zohaib_Santambrogio_Homogenate_CV10_S1_01.raw	Raw
	20240316_Lumos_OTIT_Zohaib_Santambrogio_Homogenate_CV11_S9_09.raw	Raw
	20240316_Lumos_OTIT_Zohaib_Santambrogio_Homogenate_CV20_S4_04.raw	Raw
	20240316_Lumos_OTIT_Zohaib_Santambrogio_Homogenate_CV21_S12_12.raw	Raw
	20240316_Lumos_OTIT_Zohaib_Santambrogio_Homogenate_CV23_S15_15.raw	Raw

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Project description:Neuronal overexcitability can disrupt synapse formation and strength and elicit synaptic changes which in turn give rise to neuronal hyperactivity, and eventually overall abnormal neural circuit processing. Such network disruption impairs neuronal function and survival, resulting in the onset of neurodegeneration and Alzheimer’s disease. Yet, the sequence of synaptic changes that result from sustained neuronal hyperactivity remain elusive. To address this, we adopted an optogenetic stimulation strategy to generate a model of long-lasting neuronal hyperactivity in hippocampal pyramidal neurons. We applied this to both wild-type mice and in the 5xFAD mice presenting mutations that confer susceptibility to develop Alzheimer’s disease in humans. We analyzed the proteome changes occurring after a month of daily chronic optogenetic stimulation which surprisingly revealed shared proteomic signatures between photoactivated wild-type and 5xFAD mice. Proteins involved in translation, protein transport, autophagy, and more importantly in the Alzheimer’s disease pathology were upregulated in wild-type mice. By contrast, optogenetic overdrive in the 5xFAD mice resulted in extensive downregulation of proteins participating in mRNA processing and phosphorylation. The footprint of protein change upon driving hyperactivity in the wild-type mice included downregulation of glutamatergic and GABAergic synapse proteins indicating potential disruption of synaptic transmission. Moreover, the target of rapamycin mTORC1 signaling pathway, involved in the onset of several neuropathological disorders, was hyperactive after the optogenetic activation in wild-type mice. In turn, these proteome and signalling changes in the hippocampus of wild-type mice resulted in spatial memory loss and notably augmented Αβ42 secretion. Altogether, these findings indicate that neuronal overexcitability and hyperactivity alone replicate the footprint of proteomic changes within the hippocampus seen in mice harboring Alzheimer’s disease-linked mutations. Thus, sustained neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with Alzheimer’s disease.

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Label free -DDA nano-LC/MS/MS analysis of aggregates and total hippocampal proteome in an early AD mouse model following activation of chaperone-mediated autophagy

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