# Atlas for neuronal and glial cell types selectively vulnerable to proteinopathies during progression of Alzheimer's Disease

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2023 · $2,790,703

## Abstract

Abstract
The long-term goal of this project is to elucidate multimodal mechanisms underlying selective vulnerability of
neuronal and non-neuronal cells to proteinopathies during the progression of Alzheimer's Disease (AD). The
most notable feature of AD is its strikingly age- and sex-dependent regional onset and progression–selective
vulnerability–which is manifest in distinct clinical presentations, e.g., memory impairment in AD and patterns of
brain degeneration. Recent studies on the staging of AD neuropathology showed AD-related tauopathy begins
in the locus coeruleus (LC), followed by neurofibrillary tangles in the entorhinal cortex (EC), followed by
hippocampal (HC), and then neocortex, e.g., prefrontal cortex (PFC). One hypothesis for selective vulnerability
is that major AD risk genes are regionally restricted, but the results show they are rather broadly expressed. A
body of evidence support that glia play multiple essential roles at different brain region in AD pathogenesis.
These data suggest that selective vulnerability is likely a result of interplay of intrinsic properties of neurons
and glial cells in their response to proteinopathies in a dynamic and spatiotemporal manner at vulnerable brain
regions. For example, EC neurons project multiple brain regions including the EC, PFC and cerebellum. Yet,
degeneration of EC and PFC occurs at different stages. In contrast, the cerebellum is largely not affected.
There is emerging evidence that subpopulations of microglia treat excitatory and inhibitory neurons differently.
Could different glial cell types or differential response to proteinopathies in different projecting sources and/or
targets contribute to selective vulnerability? These results underscore the central importance of understanding
the diversity of cell types and molecular signature differences in both sexes at spatiotemporal, single-cell
resolution and multimodal scales between vulnerable and less vulnerable neuronal and glial populations
susceptible to proteinopathies in AD. MAPTS305N;Int10+3 and APPNL-F knock-in (KI) AD mice displaying Tau and Aβ
proteinopathies, respectively, will be used to achieve this goal. Preliminary results were obtained to support the
project. First, barcoded single-neurons brain-wide projection mapping in controls demonstrates sex- and age-
dependent differences in projections of LC neurons to selective targets. The results showed reciprocal
innervations among these four brain regions. Second, the analysis of 16-month-old control and APPNL-F mice
showed aberrant innervation patterns by norepinephrine (NE) neurons. Third, impaired prepulse inhibition
(PPI) has been suggested to be a biomarker for prodromal AD. Importantly, PPI impairment was observed in
the 5-month-old APPNL-F mice. Finally, single nuclei (sn)-RNAseq of the EC from 16-month-old control and
APPNL-F mice showed selective loss of neuronal and non-neuronal cell types and differential expression of a list
of genes, including those assoc...

## Key facts

- **NIH application ID:** 10667245
- **Project number:** 1R01AG082151-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** KUO-FEN LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,790,703
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667245

## Citation

> US National Institutes of Health, RePORTER application 10667245, Atlas for neuronal and glial cell types selectively vulnerable to proteinopathies during progression of Alzheimer's Disease (1R01AG082151-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10667245. Licensed CC0.

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