Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease

Cary, G. A.; Young, J. E.; Rose, S. E.; Frankowski, H.; Darvas, M.; Bothwell, M.; Jayadev, S.; Reid, A. N.; Greenwood, A.; Levey, A.; Leal, K.; Carter, G. W.; Wiley, J. C.

doi:10.1101/2025.09.13.676046

bioRxiv · 10.1101/2025.09.13.676046

Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease

Cary, G. A.·Young, J. E.·Rose, S. E.·Frankowski, H.·Darvas, M.·Bothwell, M.·Jayadev, S.·Reid, A. N.·Greenwood, A.·Levey, A.·Leal, K.·Carter, G. W.·Wiley, J. C.

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Abstract

BACKGROUNDAlzheimers disease (AD) is associated with amyloid plaques and can be caused by autosomal dominant mutations in APP or PSEN1/2, which form an enzyme substrate complex. Decreases in catalysis of AD mutant APP and PSEN1 supports the hypothesis that membrane delimitation of KAT5 could contribute to AD. METHODSWe compare the hippocampal transcriptome profiles of the Kat5 brain-specific knockout mouse to multiple AD datasets through alignment with the TREAT-AD AD biological domains. We examine KAT5 subcellular localization in human WT and AD neurons. RESULTSThe 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. DISCUSSIONThis analysis supports the hypothesis that KAT5 nuclear signaling down stream of APP cleavage plays a pivotal role in neuronal homeostasis and immune regulation.

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Cary, G. A., Young, J. E., Rose, S. E., Frankowski, H., Darvas, M., Bothwell, M., Jayadev, S., Reid, A. N., Greenwood, A., Levey, A., Leal, K., Carter, G. W., Wiley, J. C.. 2025-09-17. Kat5 cKO Biological Domain Signatures Align with Human Alzheimer Disease. https://doi.org/10.1101/2025.09.13.676046

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