# Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $516,281

## Abstract

We aim to prevent Alzheimer disease (AD) in adults with DS (trisomy 21), referred to as AD in DS (AD-DS) by
enhancing processing of the amyloid precursor protein (APP) to reduce the levels of the C-terminal 99 residue
fragment (C99) and Aβ42. The therapeutic premise is based on: 1) increased APP gene dose is necessary for
AD-DS, a finding replicated in mouse models of DS. By normalizing APP dose in DS models we eliminated: a)
age-related degeneration of neurons in locus coeruleus (LCNs) and basal forebrain complex (BFCNs), b) hyper-
phosphorylation of Tau, and c) enlargement of early endosomes; 2) increased C99 and Aβ42 acted via increased
activation of Rab5 to induce changes in endosomes resulting in reduced trafficking of neurotrophic signals and
BFCN atrophy. The evidence suggests that increased C99 and Aβ42 cause degeneration via deficits in
endosomal trafficking of neurotrophic signals and motivates treatments to reduce C99 and Aβ42. Because both
are substrates for γ-secretase, increasing γ-secretase activity should decrease levels and prevent or mitigate
endosomal and degenerative phenotypes. BPN15606, a γ-secretase modulator (GSM), increases γ-secretase
activity. In vitro, BPN15606 potently reduced C99 and Aβ42, reduced Rab5 activation and restored endosome
size and trafficking of neurotrophins. In vivo, it reversed endosomal enlargement, improved LCN number,
reversed Tau hyper-phosphorylation and enhanced cognition. In mouse models of AD-DS and AD/cerebral
amyloidosis we will test the therapeutic hypothesis that BPN15606 will reduce the levels of C99 and Aβ42
to prevent and/or lessen neurodegeneration. The mechanistic hypothesis tested is that BPN15606 will
normalize endosomal structure and function, neurotrophin signaling and trafficking, and improve
cognition. Extensive pharm/tox studies qualify BPN15606 for our studies. Specific Aims: 1. To detail the time of
onset of neurodegeneration in mouse models of AD-DS and AD/cerebral amyloidosis. Studies of the Dp16 model
of AD-DS and Line 41 model of AD will be submitted to unbiased stereological studies of morphology and
biochemistry, to quantitatively define onset of degeneration of neurons and synapses (Dp16: LCNs, BFCNs; Line
41: BFCNs, CA3), emergence of p-Tau and amyloid plaques. 2. To examine the effect of BPN15606 treatment
before and after onset of neurodegeneration in the AD-DS model. Dp16 and 2N mice will be treated with an
effective, safe dose of BPN15606. Guided by quantitative GO/NOGO criteria, the extent to which enhanced APP
processing results in lessening of degenerative, endosomal and cognitive phenotypes will be assessed. 3. To
examine the effect of BPN15606 treatment before and after onset of neurodegeneration in the AD/cerebral
amyloidosis model. The same approach will guide BPN15606 studies in the Line 41 mouse. BPN15606-mediated
reductions in degeneration will support the therapeutic hypothesis; normalization of endosomal and cognitive
phenotypes will support the mechan...

## Key facts

- **NIH application ID:** 10338158
- **Project number:** 5R01AG055523-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** William C Mobley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $516,281
- **Award type:** 5
- **Project period:** 2018-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338158

## Citation

> US National Institutes of Health, RePORTER application 10338158, Treating with Gamma-Secretase Modulators to Prevent Neurodegeneration in Mouse Models of Down Syndrome and Alzheimer Disease (5R01AG055523-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10338158. Licensed CC0.

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