Alzheimer's disease (AD) is a highly prevalent form of dementia and one of the largest public health challenges
worldwide. Thus, developing early interventions to prevent or delay AD progression is vital. Neuronal network
dysfunction is an early characteristic of AD, observed in people at risk of developing this disorder, and has
been linked to abnormal activity of cortical parvalbumin (PV) containing interneurons. Another early
characteristic of AD is sleep abnormalities, observed years before the onset of cognitive impairment. While
both these issues develop during early stages of AD and are potential factors that exacerbate subsequent AD
pathogenesis, the relationship between abnormal PV neuron activity and sleep impairment has not been
investigated. The overarching hypothesis here is that abnormal excitability of PV neurons during the early
stage of AD is responsible for impaired sleep oscillations, further accumulation of amyloid-β (Aβ), and impaired
cognition. Thus, early interventions, correcting PV abnormalities could prevent sleep disturbances, slow down
Aβ accumulation, and prevent memory deficits in AD. The proposed experiments utilize well-established AD
mouse models (APP/PS1 and 5XFAD) and focus on the medial prefrontal cortex (mPFC), an area critical for
generation of non-rapid-eye-movement (NREM) slow waves and one of the earliest regions to accumulate Aβ,
and the hippocampus (HPC) which is vital for learning and memory and altered in AD. Previous in vitro studies
using these AD mouse models reported findings regarding PV abnormalities which appear to contradict each
other. Thus, Aim 1 of this proposal will use the state-of-the-art fiber photometry technique, along with local field
potential recordings in vivo to longitudinally characterize how neuronal activity in PV neurons and pyramidal
neurons change, and how changes in PV interneurons relate to sleep oscillations across early to later stages
of AD in the two mouse models with different timecourses of AD pathology. Aim 2 will assess the therapeutic
benefit of sustained manipulation of PV neurons via chemogenetics on sleep oscillation abnormalities, Aβ
level, and behavior (HPC-dependent memory). If successful, this work will identify the timing of AD-related
disruption of cortical network activity, sleep oscillation biomarkers and inform early intervention strategies to
prevent or delay AD progression. The training plan for this award includes mentorship from an expert team of
Harvard Medical School/VA Boston faculty specializing in sleep research, cortical oscillations, neuroanatomy,
and AD. Faculty investigators from Boston University/VA Boston and the Massachusetts Alzheimer's Disease
Research Center will provide comprehensive training on AD research in humans and in mouse models. The
proposed technical and conceptual training in fiber photometry and histochemical assay for AD pathology, as
well as didactic courses and workshops relevant to AD and professional development will facilitate the
applicant's goal of becoming an independent investigator in the AD research field.