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• W4387504210 abstract "Mutations in the Presenilin (PSEN1 and PSEN2) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD PSEN1 mutations exhibit impaired γ-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing γ-secretase activity and is located closest to the active site of γ-secretase. Here, we report that introduction of the codon-optimized wild-type human PSEN1 cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired γ-secretase activity in the cerebral cortex of Psen mutant mice either lacking PS or expressing the Psen1 L435F KI allele, as evaluated by endogenous γ-secretase substrates of APP and recombinant γ-secretase products of Notch intracellular domain and Aβ peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in Psen mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged Psen mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired γ-secretase activity, synaptic and memory deficits, and neurodegeneration caused by Psen mutations in mouse models." @default.
• W4387504210 created "2023-10-11" @default.
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• W4387504210 date "2023-10-10" @default.
• W4387504210 modified "2023-10-12" @default.
• W4387504210 title "Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in <i>Psen</i> mutant mice" @default.
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• W4387504210 doi "https://doi.org/10.1073/pnas.2306714120" @default.
• W4387504210 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37816062" @default.
• W4387504210 hasPublicationYear "2023" @default.
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