Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Kat5 cKO mouse replicates biological domain signatures associated with Alzheimer's disease.
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Cary Greg A, Young Jessica E, Rose Shannon E, Frankowski Harald, Wilkins Heather, Amirtha Ganesh Sai Sruthi, Draper Julia, Darvas Martin, Bothwell Mark, Jayadev Suman, Reid Aquene N, Greenwood Anna, Levey Allan I, Leal Karina, Carter Gregory W, Wiley Jesse C
Аннотация
INTRODUCTION: Alzheimer's disease (AD) can be caused by autosomal-dominant familial Alzheimer's disease (FAD) mutations in amyloid precursor protein (APP) or presenilin-1 and 2, which form an enzyme substrate complex. KAT5 binds to the APP intracellular domain. Recent reports of decreased γ-secretase activity in FAD mutants support KAT5 membrane sequestration.
METHODS: We compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout (KO) mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human wild-type and AD neurons.
RESULTS: The Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle, and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons.
DISCUSSION: This analysis supports the hypothesis that KAT5 nuclear signaling downstream of APP cleavage plays a pivotal role in neuronal homeostasis.
METHODS: We compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout (KO) mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human wild-type and AD neurons.
RESULTS: The Kat5 KO mouse demonstrates downregulation of synaptic genes, metabolic pathways, and upregulation of DNA replication and repair, cell cycle, and immune response genes. We see similar profiles in Kat5 and comparative AD datasets. KAT5 is restricted to the cytosol in human AD neurons.
DISCUSSION: This analysis supports the hypothesis that KAT5 nuclear signaling downstream of APP cleavage plays a pivotal role in neuronal homeostasis.