Abstract Details

Assess the therapeutic potential of DNAJC5 in Alzheimer’s disease (AD).

N2A695 cells stably expressing mutant DNAJC5 or knocking down endogenous Dnajc5 were analyzed through immunoblotting and ELISA for APP processing and Aβ production. Brains of ANCL patients and Dnajc5+/-; 5xFAD mice were assessed for amyloid pathology with immunohistochemistry. Transcriptomics from ANCL, AD, and control brains was analyzed for differentially expressed genes (DEGs). The Clue.IO database was used to identify potential targets for gene therapy or pharmacological intervention.

ANCL-patient brains exhibited low soluble or insoluble Aβ levels, but intra-neuronal Aβ accumulation. They exhibited reductions in synaptic protein levels (SNAP-25, Synaptobrevin, Syntaxin 1, and Synaptophysin). Transcriptomic analysis of ANCL-patient brains showed reduced TSPAN14, which facilitates ADAM10 maturation, elevated APH1B, a γ-secretase subunit, and elevated GSAP, the γ-secretase activating protein. There were 67 upregulated and 15 downregulated transcripts associated with processes essential for synaptic function, including the MAPK cascade (FYN, SOS1), dendritic spine organization (FYN), and endosomal vesicle fusion (VPS11, VPS39). Clue.IO identified heat-shock protein inhibitors and an opioid receptor antagonist (BNTX) as potential pharmacological agents to counteract the effects of mutant DNAJC5. AD patients and 5xFAD mice exhibited reduced DNAJC5 expression. Preliminary results from Dnajc5+/-; 5xFAD mice showed increased plaques in the corpus collosum and hippocampus. N2A695 cells expressing DNAJC5 mutants showed increased Aβ while DNAJC5 knockdown decreased Aβ.

Low levels of CSPα alter Ab secretion and dysregulate genes and synaptic proteins, suggesting that increasing CSPα levels could reduce Aβ and improve synaptic function.