# BACE1 in neurodegeneration and neuronal dysfunction

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $530,047

## Abstract

ABSTRACT
BACE1 was discovered as the Alzheimer's β-secretase for initiating the production of β-amyloid peptide (Aβ)
from amyloid precursor protein (APP). Abnormal accumulation of Aβ in various forms (dimers, trimers,
multimers, oligomers) has been linked to impaired synaptic and cognitive functions in Alzheimer's disease (AD)
patients. Reducing Aβ generation by BACE1 inhibition is therefore an actively investigated area for
ameliorating cognitive dysfunction in AD patients. However, BACE1, as a membrane-bound aspartyl protease,
can cleave membrane-bound proteins other than APP. Among its identified substrates, the signaling molecule
neuregulin-1 (Nrg1) and Notch ligands such as Jagged-1 (Jag1) are important for their roles in neural
development and synaptic functions. In this study, we will focus on the roles of BACE1 in processing signaling
molecules such as Nrg1 and Jag1. The abolished cleavage of Nrg1 in BACE1-null mice reduces Nrg1
signaling through ErbB receptors and thus impairs myelination during development and remyelination in the
adult, and it also induces schizophrenia-like behaviors, including impaired cognitive functions. On the other
hand, abolished cleavage of Jag1 in BACE1-null mice likely increases Jag1 signaling on the neuronal surface
and activation of its receptor Notch in a paracrine fashion; this increased Jag1-Notch signaling induces
astrogenesis and reduces neurogenesis in the subgranular zone (SGZ). Neurogenesis in the SGZ produces
dentate granule cells, which are neurons important for long-term potentiation. Hence, BACE1 is required for
normal neural development and synaptic functions. We aim to test our central hypothesis that BACE1
cleavage of signaling molecules such as Nrg1 and Jag1 regulates neurogenesis and synaptic
functions. Specifically, we will 1) determine the role of BACE1-dependent Nrg1 signaling in the control of
synaptic function, and 2) investigate BACE1-dependent Jag1 signaling in astrogenesis and neurogenesis. Our
main objectives for accomplishing the proposed studies are to fully understand the in vivo neuronal functions
that BACE1 exerts during early development and in the adult brain and to develop strategies for enhancing
synaptic functions or neurogenesis to couple with therapeutic strategies of reducing Aβ through BACE1
inhibition in AD patients.

## Key facts

- **NIH application ID:** 9931310
- **Project number:** 5R01NS074256-10
- **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:** 2020
- **Award amount:** $530,047
- **Award type:** 5
- **Project period:** 2011-05-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931310

## Citation

> US National Institutes of Health, RePORTER application 9931310, BACE1 in neurodegeneration and neuronal dysfunction (5R01NS074256-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9931310. Licensed CC0.

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