Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma and cellular pathologies is unclear. Here, we show reduced behaviorally-driven gamma before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease (AD). Optogenetically driving FS-PV-interneurons at gamma (40 Hz), but not other frequencies, reduced levels of amyloid-β (A β)1-40 and A β1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia and histological analysis confirmed increased microglia co-localization with A β. Subsequently, we designed a non-invasive 40 Hz light-flickering paradigm that reduced A β1-40 and A β1-42 levels in visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate AD-associated pathology.

The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. VIDEO ABSTRACT.

Highlights d Auditory gamma entrainment using sensory stimuli (GENUS) boosts hippocampal function d GENUS affects microglia, astrocytes, and vasculature in auditory cortex and hippocampus d Auditory plus visual GENUS induces microglia clustering around plaques d Auditory plus visual GENUS reduces amyloid pathology throughout neocortex

No abstract