# Role of BMP Signaling in the Aging Brain R01 AG054429

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $359,772

## Abstract

Aging is the leading risk factor for developing sporadic Alzheimer’s disease (sAD) suggesting that
the aging process is linked to the pathophysiology of the disease. The aging process is highly
variable, and some aged individuals develop non-degenerative cognitive impairment while others
are resilient. The biological basis of this heterogeneity is unknown. However, aging is associated
with biochemical and morphological changes that may shed insight into the both the phenotypic
heterogeneity in aging and the age-related susceptibility to AD. In particular, changes in
hippocampal structure and connectivity are associated with aging. Among these changes is a
decline in neurogenesis in the dentate gyrus (DG) with decreased performance on hippocampus-
dependent cognitive tasks. BMP signaling in the brain increases dramatically with age, and we
have been exploring the hypothesis that this underlies aging-related changes neurogenesis and
cognition. BMP signaling and neurogenesis are also both altered significantly in AD. However, it
is unclear whether changes in BMP signaling and in neurogenesis in AD are an exacerbation of
the aging process or rather due to unrelated mechanisms. The goal of this proposed supplement
is to use both the knowledge and the tools developed as part of our ongoing studies of the role of
BMP signaling in the aging brain to define the role of this signaling pathway in the development
of AD. Second to age, the human apolipoprotein E (hAPOE) genotype is the strongest known risk
factor for sAD. Further, in aging mice, neuronal expression of the ε4 isoform results in neuron
loss and impaired learning and memory, and APOE regulates hippocampal neurogenesis. The
convergence of the effects of the aging related increase in BMP signaling and of APOE on
cognition and on neurogenesis suggest possible interactions between the aging related increase
in BMP signaling, APOE genotype, and the development of sAD. Specifically, we hypothesize
that the aging related increase in BMP signaling in brain predisposes neurons to the effects of
APOE4 and to development of AD, and that that it explains, at least in part, why aging is the
greatest risk factor for sAD. We will use the iPSC lines we derived from sAD patients to explore
interactions between APOE genotype and BMP signaling on tau phosphorylation, amyloid ß
secretion, and neurite preservation, and on neuronal survival after increasing calcium influx in
neurons derived from the iPSCs. We also will examine the role of BMP signaling in development
of pathology and of behavioral changes in 5XFAD mice.

## Key facts

- **NIH application ID:** 10121093
- **Project number:** 3R01AG054429-04S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** JOHN A KESSLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $359,772
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121093

## Citation

> US National Institutes of Health, RePORTER application 10121093, Role of BMP Signaling in the Aging Brain R01 AG054429 (3R01AG054429-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10121093. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*