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Loss of Smell and the Olfactory-Hippocampal Gamma Oscillation Changes in the Acceleration of Alzheimer's Disease Progression

Joseph A.Villanueva1, 2, Maria A.Nagel2, 3, Diego Restrepo1, 2, 4.

1Department of Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.2Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.3Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.4Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Abstract


Alzheimer’s disease (AD) brain pathology includes deposition of β-amyloid (Aβ) plaques, phosphorylated-tau, neurofibrillary tangles, and microglial activation that lead to reduced gamma oscillation power and cognitive impairment (Murty D., 2021). Indeed, multi-sensory stimulation at 40 Hz reduces amyloid burden and increases microglial co-localization with Aβ (Iaccarino, HF., 2016). Loss of smell has emerged as an early feature of AD where decreased smell is linked to faster brain volume loss and cognitive decline (Murphy, C., 2019). Further, sniff-induced gamma oscillations from the olfactory bulb (OB) to the hippocampus suggest that loss of smell decreases hippocampal gamma oscillations. I hypothesize that stimulation of the OB in gamma frequencies will ameliorate AD pathologies by recruiting CD4+ T-cells and shifting microglia to a non-disease like states as well as improve learning and memory in a familial AD mouse model. I present optogenetic studies using OMP-hChR2V mice to stimulate olfactory sensory neurons and entrain the hippocampus in gamma oscillations. LFP recordings in the OB and dorsal CA1 show robust coupling to CA1. In a chemogenetic approach, I express the excitatory DREADD receptor, hM3Dq in CaMKIIa mice granule cells to enhance synchronous gamma firing (Dalal and Haddad, 2022). Oscillatory power changes were dose-dependent of the hM3Dq ligand, clozapine-N-oxide. At a high dose, there was a CA1 gamma power decrease, while at a medium dose, a transient increase followed by a decrease in gamma power in CA1 was observed. These findings contribute to the understanding of the therapeutic effects of gamma frequency stimulation on AD pathology via an intranasal route. Funded by an NIA administrative supplement to R01 DC000566, R01 AG079193 and T32 DC012280

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