Abstract
AbstractAlzheimer’s disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for a better understanding of the disease mechanisms; yet the specific mechanism of action for those genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Using CRISPR/Cas9 gene editing, we generated a knockout model forabca7,orthologous to humanABCA7 –an established AD-risk gene. Theabca7+/-zebrafish showed reduced astroglial proliferation, synaptic density, and microglial abundance in response to amyloid beta 42 (Aβ42). Single-cell transcriptomics revealedabca7-dependent neuronal and glial cellular crosstalk through neuropeptide Y (NPY) signaling. Theabca7knockout reduced the expression ofnpy, bdnfandngfra, which are required for synaptic integrity and astroglial proliferation. With clinical data in humans, we showed reducedNPYin AD correlates with elevated Braak stage, predicted regulatory interaction betweenNPYandBDNF, identified genetic variants inNPYassociated with AD, found segregation of variants inABCA7, BDNFandNGFRin AD families, and discovered epigenetic changes in the promoter regions ofNPY, NGFRandBDNFin humans with specific single nucleotide polymorphisms inABCA7. These results suggest that ABCA7-dependent NPY signaling is required for synaptic integrity, the impairment of which generates a risk factor for AD through compromised brain resilience.Abstract FigureGraphical abstract
Publisher
Cold Spring Harbor Laboratory