# Inhibition of BACE1 for benefiting Alzheimer's patients

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $777,423

## Abstract

Abstract
BACE1 is an enzyme required for Aβ generation, and chemical inhibition of BACE1 has been
explored for reducing Aβ generation. Five brain-penetrable BACE1 inhibitory dugs were recently
tested in human trials. Unfortunately, despite a noted reduction in Aβ plaque loads, these clinical
trials were terminated, largely due to neuronal and synaptic toxicity. This setback indicates the
importance to known more BACE1 biology and to develop safer BACE1 inhibitors for AD
treatment, especially considering the growing evidence from anti- Aβ trials that reducing Aβ
plaques early can lead to reduction of other AD pathologies. In this proposal, we aim to test a
novel hypothesis that increasing inhibition of BACE1 in glial cells, along with boosting microglial
phagocytic functions, will reduce AD pathologies while minimizing synaptic side effects. This
hypothesis is supported by our recent observations that Bace1 deletion in microglia facilitates the
transition of homeostatic microglia to more phagocytic stage-1 disease-associated microglia
(DAM-1). Consistently, deletion of microglial Bace1 in 5xFAD mice reduces amyloid deposition.
If Bace1 in astrocytes is deleted, the expression of genes, such as clusterin (Clu), CXCL14 and
ApoE, important for removal of amyloid plaques by astrocytes, is increased. These results
suggest that BACE1 inhibition in glial cells has a beneficial effect on the clearance of amyloid
plaques. However, many questions remain to be answered. For example, it is not clear whether
Bace1 deletion will affect tau pathology. We do not yet know how BACE1 inhibition will enhance
microglia to remove tau pathology. Considering the known role of chemoattractant molecule
CXCL14 in mediating migration of immune cells and reduced levels of CXCL14 in AD brains, we
will ask whether the expected elevated levels of CXCL14, in response to the inhibition by BACE1,
will promote phagocytic function of microglia. This question will be address by utilizing an
inducible transgenic mouse model that has already been generated. In this proposal, we will
explore whether deletion of BACE1 in PS19 mouse microglia will reduce tau pathology in Aim 1.
In Aim 2, we will ask whether a low dose inhibition of BACE1 in AD triple-transgenic model
coupled with deletion of Bace1 in microglia will reduce both amyloid and tau pathologies
effectively. In Aim 3, we will investigate whether enhancing expression of CXCL14 will promote
microglia migration and phagocytosis. These studies are centered on improving microglia function
and the knowledge gained from this study will help to develop a therapeutic approach that will
favor BACE1 inhibition in glial cells coupled with molecular boosters of microglia phagocytic
function for AD treatment.

## Key facts

- **NIH application ID:** 10981469
- **Project number:** 2R01AG046929-07A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** RIQIANG YAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $777,423
- **Award type:** 2
- **Project period:** 2013-09-30 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981469

## Citation

> US National Institutes of Health, RePORTER application 10981469, Inhibition of BACE1 for benefiting Alzheimer's patients (2R01AG046929-07A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10981469. Licensed CC0.

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