# APOE4 Increases Astrocytic Tau Internalization to Promote Alzheimer’s-Related Neuronal Pathology

> **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $23,657

## Abstract

PROJECT SUMMARY/ABSTRACT
 The aim of this proposal is to provide the trainee, who has a physiology background, with training in
molecular and cellular neurobiology and enable her transition to a post-doctoral position in neurodegenerative
therapeutics. The rich training environment, which includes a strong mentoring team of diverse scientists, will
equip the trainee with the expertise needed to successfully evaluate cell-type-specific immunometabolic
mechanisms that impact tau pathology and neuroinflammation in the context of Alzheimer’s disease (AD).
 The objective of this proposal is to investigate the influence of cholesterol on astrocytic internalization of tau
and the subsequent effect this has on neuronal health and viability. Primary astrocyte and neuron cultures from
humanized apolipoprotein E (APOE) ε3 and ε4 mice will be used to test the overall hypothesis that the higher
cholesterol levels inherent to APOE ε4 carriers increase tau internalization in astrocytes, evoking astrogliosis
and subsequent diminished neuronal health via altered immune and metabolic function.
 The hypothesis of Aim 1 is that higher astrocytic cholesterol levels increase internalization of tau. To test
this, astrocytes stimulated with recombinant tau monomers or aggregates will be evaluated for changes in tau
internalization before and after pharmacological modulation of cholesterol levels. Phagocytic inhibitors will be
used to evaluate the mechanism of internalization as well as to compare cholesterol-related effects on
internalization. Astrocytes from APOE ε3 and ε4 mice will be used to compare the differences in astrocytes
expressing the most common APOE isoform verses the AD risk isoform.
 The hypothesis of Aim 2 is that tau increases APOE ε4 astrocytic inflammatory cytokine secretion, in turn
decreasing neuronal health. To test this, astrocytes stimulated with recombinant tau will be assayed by a
multiplex cytokine panel to identify an inflammatory signature. Conditioned astrocytic media, as well as cytokines
identified to have altered expression, will be used to stimulate primary neurons and their responses will be
evaluated by metabolic, synaptic, and viability measures.
 Achievement of these aims will drive the field of tauopathy-related disease research forward by determining
whether cholesterol levels modulate internalization of tau in astrocytes, and if secondary release of
proinflammatory cytokines from astrocytes to neurons due to tau stimulation triggers diminished neuronal health.
Understanding the influence of APOE isoform status on tau-related pathology will improve scientific knowledge
of mechanisms of AD progression. More specifically, this knowledge will be impactful in identifying the role APOE
ε4 genetic risk plays in potentiating AD pathology through loss of astrocytic support to neurons. These findings
will provide rationale for identification of novel treatment targets for prevention of tau propagation, astrogliosis,
and subsequent neurode...

## Key facts

- **NIH application ID:** 10388542
- **Project number:** 1F31AG071131-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Rebecca M Fleeman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $23,657
- **Award type:** 1
- **Project period:** 2022-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388542

## Citation

> US National Institutes of Health, RePORTER application 10388542, APOE4 Increases Astrocytic Tau Internalization to Promote Alzheimer’s-Related Neuronal Pathology (1F31AG071131-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10388542. Licensed CC0.

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