Project Summary The primary objective of the proposal is to identify the initial regions in the brain affected by Alzheimer's disease (AD), focusing on the entorhinal cortex (EC) and locus coeruleus (LC). These areas are known to accumulate tau pathology, leading to cognitive impairment. The researchers plan to use advanced techniques to record the electrophysiological properties of EC and LC neurons in App knockin mice, aiming to understand how pathology contributes to neuronal dysfunction, sleep disruption, and memory impairment. They also intend to use new tools for visualizing gene expression in intact tissue using spatial transcriptomics, specifically 10X Visium technology, to study transcriptomic changes in these vulnerable brain regions. The proposal includes two specific aims: Aim 1 involves the transcriptomic analysis of the LC region in AD mice, with the goal of understanding how tauopathy affects the electrophysiological properties of the LC and downstream regions. The researchers expect to see changes in genes related to novelty response, arousal, and sleep. Aim 2 focuses on the transcriptomic analysis of the MEC region in AD mice, aiming to understand how amyloid beta and tau pathology change gene expression in the MEC. The researchers anticipate changes in genes involved in maintaining memory processes. These aims will provide valuable transcriptomic profiling of the two vulnerable brain regions, significantly benefiting the parent proposal.