# Cell-type-specific vulnerability of the entorhinal cortex in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $392,500

## Abstract

Abstract
Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the U.S.,
a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic
mental functions, but severely batters families and caregivers. Its annual costs are currently estimated at $236
billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need to combat
AD grows increasingly pressing. Histological and imaging studies in AD patients and animal models have shown
that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. Inside the
entorhinal cortex, neurons in layer II are known to undergo earliest neurodegeneration. However, it is still largely
unclear what cell type in layer II of the entorhinal cortex exhibits such neurodegeneration. Our preliminary results
and recent literature suggest a possibility that layer II neurons show cell-type-specific vulnerability to
neurodegeneration. Here we propose studies to characterize the cell-type-specific neurodegeneration of layer II
neurons in the entorhinal cortex, and to investigate the circuit mechanisms by which cell-type-specific cell death
causes memory impairment in AD. Our approach involves cell-type-specific histological analyses, cell-type-
specific in vivo recording of spike activity, cell-type-specific optogenetic and chemogenetic methods, and a novel
APP knock-in mouse model. There are three Specific Aims: (Aim 1) To identify histological and molecular
properties of degenerating entorhinal cortex neuronal types in APP-KI mice; (Aim 2) To identify in vivo
electrophysiological spike activities of entorhinal cortex cell types; and (Aim 3) To determine the effect of
entorhinal neurodegeneration on hippocampal place cell activity and on memory loss of APP knock-in mice. If
successful, our studies will identify cellular and circuit mechanisms of cell-type-specific neurodegeneration in the
entorhinal cortex in AD. Such knowledge of entorhinal cell-type-specific vulnerability is expected to be a
breakthrough for future identification of therapeutic targets to prevent or slow AD progression.

## Key facts

- **NIH application ID:** 10343783
- **Project number:** 5R01AG066806-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Kei M Igarashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343783

## Citation

> US National Institutes of Health, RePORTER application 10343783, Cell-type-specific vulnerability of the entorhinal cortex in Alzheimer's disease (5R01AG066806-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10343783. Licensed CC0.

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