# The role of ectodermal-neural cortex 1 in selective neuronal vulnerability in aging and Alzheimer's disease

> **NIH NIH R56** · OHIO STATE UNIVERSITY · 2020 · $498,043

## Abstract

Project Summary/Abstract:
Excitatory (EX) neurons are preferentially vulnerable in aging and early Alzheimer’s disease (AD), the most
common form of dementia. The molecular determinants of this selective vulnerability are unclear. We recently
identified ectodermal-neural cortex 1 (ENC1), a Kelch-related actin-binding protein, as being differentially
expressed in EX neurons and one of master regulator genes responsible for selective neuronal vulnerability to
tau pathology in AD. In culture models, upregulation of ENC1 has been shown to be detrimental for neural
survival through its downregulation of a redox sensitive transcription factor, nuclear factor erythroid 2 like 2
(NFE2L2/NRF2) and/or its downregulation of the autophagic flux pathway through interaction with
phosphorylated Sequestosome 1 (SQSTM1/p62). Furthermore, a single-nucleus transcriptomic analysis shows
that ENC1 is enriched in the subpopulation of EX neurons associated with AD pathology. Comparing the gene
signatures of single cells isolated from donors with early AD pathology to those without AD pathology, we
found that the mRNA level of ENC1 is significantly lower in EX neurons, astrocytes and oligodendrocytes,
whereas it does not change significantly in other types of cells. The decreased level of ENC1 in AD may
indicate vulnerable cells are trying to mitigate compromised protein homeostasis by the downregulation of
aggregation-prone proteins like ENC1. Controversially, ENC1 has also been suggested to determine cognitive
resilience (i.e. less vulnerable) in the aging population, and is implicated in the NRF2-dependent oxidative
stress response after treatment with hydrogen peroxide. However, the exact role of ENC1 in selective neuronal
vulnerability in aging and early AD remains unclear. We hypothesize that EX neuron- and astrocyte-
specific downregulation of ENC1 may protect or ameliorate the degeneration of EX neurons in aging
and AD through the upregulation of the NRF2-p62 autophagy pathway. To test this hypothesis, this
proposal will (1) identify if manipulation of ENC1 level in primary cultured neurons and human cerebral
organoids will affect the vulnerability to tau pathology, electrophysiological properties, and the NRF2-p62
autophagy pathway; (2) determine if cell-type specific knockdown of ENC1 in animal models will upregulate the
NRF2-p62 autophagy pathway, and ameliorate the aging phenotype, AD pathology, and cognitive deficits; and
(3) define the relationship between ENC1 and Nrf2-p62 autophagy pathway in aging and AD. Identifying the
cell-autonomous (neurons) and/or cell non-autonomous (astrocytes) role of ENC1 in selective neuronal
vulnerability in aging and early AD could aid in the discovery of novel drug targets that can be targeted to
protect vulnerable neurons from degeneration in aging and early AD. In addition, the approaches proposed to
characterize cell populations vulnerable to pathological proteins in AD can be applied to a wide range of
degenerative dis...

## Key facts

- **NIH application ID:** 10236580
- **Project number:** 1R56AG066782-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Hongjun Fu
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,043
- **Award type:** 1
- **Project period:** 2020-09-17 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236580

## Citation

> US National Institutes of Health, RePORTER application 10236580, The role of ectodermal-neural cortex 1 in selective neuronal vulnerability in aging and Alzheimer's disease (1R56AG066782-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236580. Licensed CC0.

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