Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits
Year: 2024
Type: article
Abstract: Rare mutations in the gene encoding presenilin2 (PSEN2) are known to cause familial Alzheimer’s disease (FAD). Here, we explored how altered PSEN2 expression impacts on the amyloidosis, endolysosomal abnormalities, and synaptic dysfunction observed in female APP knock-in mice. We demonstrate that PSEN2 knockout (KO) as well as the FAD-associated N141IKI mutant accelerate AD-related pathologies in female mice. Both models showed significant deficits in working memory that linked to elevated PSEN2 expression in the hippocampal CA3 region. The mossy fiber circuit of APPxPSEN2KO and APPxFADPSEN2 mice had smaller pre-synaptic compartments, distinct changes in synaptic vesicle populations and significantly impaired long term potentiation compared to APPKI mice. At the cellular level, altered PSEN2 expression resulted in endolysosomal defects and lowered surface expression of synaptic proteins. As PSEN2/γ-secretase is restricted to late endosomes/lysosomes, we propose PSEN2 impacts endolysosomal homeostasis, affecting synaptic signaling in AD-relevant vulnerable brain circuits; which could explain how mutant PSEN2 accelerates AD pathogenesis. This latest research reveals that changes in PSEN2 expression accelerate amyloid build-up, disrupt lysosomal function, and weaken synaptic connections. These findings spotlight PSEN2 as a powerful target for early Alzheimer’s disease intervention.
Source: Nature Communications
Institutions: VIB-KU Leuven Center for Brain & Disease Research, KU Leuven
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: 3D SUper-Resolution to cryo-Electron MIcroscopy to study nanoscale subcellular dynamics and structure that alter in Neurodegenerative Diseases - 3SURE MIND, Decoding neuron- and microglial-specific molecular mechanisms underlying Presenilin2 function in familial Alzheimer's disease, Proteolytic Surveillance of signalling molecules in the membrane: unraveling the mechanisms and endogenous regulation of aspartyl intramembrane proteases., How risk genes of late-onset Alzheimer’s disease contribute to the outset of lysosomal homeostasis impairment in neurons at early stages of the neuropathogenic cascade: the case of PLD3.
OpenAlex ID: W4404839345