# Role of MAMs in stabilization and BACE1-mediated processing of palAPP.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $408,920

## Abstract

The amyloid precursor protein (APP) undergoes sequential proteolysis by β- and γ-
secretases to produce amyloid β (Aβ) in Alzheimer's disease (AD). Currently, clinical trials
are underway targeting Aβ with β- or γ-secretase inhibitors in mild or prodromal AD
patients. Alternative Aβ-lowering agents are also being actively pursued. Along these
lines, we previously demonstrated that Acyl-coenzyme A: cholesterol acyltransferase
(ACAT) inhibitors, e.g. CP-113,818 and CI-1011, which prevent conversion of cholesterol
into cholesteryl-esters, reduce secreted Aβ levels by up to 92%, and improve AD-like
pathology in hAPP transgenic mice. ACAT-inhibitors have not been clinically developed
for AD largely because the molecular mechanism regarding effects on Aβ generation
remains unclear. We have demonstrated, for the first time, that approximately 10% of APP
is post-translationally modified by palmitic acid in vitro and in vivo. Palmitoylated APP
(palAPP) is enriched in cholesterol-rich lipid rafts where it appears to serve as a preferred
substrate for β-secretase (BACE1) versus total APP. ACAT-inhibition decreased lipid raft
palAPP levels by up to 76%. We have also reported that ~90% of palAPP forms cis-
dimers undergoing preferred BACE1 cleavage in detergent resistant membranes (DRMs).
Thus, palAPP and/or cis-dimerized palAPP in lipid rafts are potentially useful drug targets
for AD. Recently, we reported that palAPP is also enriched in raft-like Mitochondria-
associated ER Membranes (MAMs) in vitro and in vivo, together with BACE1, γ-secretase,
and ACAT. Interestingly, MAM function and ER–mitochondrial communication are
increased significantly in fibroblasts from both familial and sporadic AD patients. Overall,
our preliminary studies indicate that palAPP is synthesized in neuronal cells including
neuronal processes and is stabilized in MAMs. Thus, we propose the following
hypothesis: palAPP that is stabilized in MAM's undergoes BACE1 cleavage in
neuronal cells and processes. We will explore the effects of novel ACAT inhibitors on
palAPP trafficking and processing in MAM-associated/stabilized palAPP, including the use
of live-cell imaging and cell surface biotinylation assays in primary neurons and our 3D
human stem cell-derived neural culture models. The overarching goal of this proposal is to
generate the necessary mechanistic and in vivo data to further the development of novel
therapeutic strategies for AD by targeting ACAT and MAM-associated palAPP.

## Key facts

- **NIH application ID:** 10210441
- **Project number:** 5R01NS045860-19
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RUDOLPH Emile TANZI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,920
- **Award type:** 5
- **Project period:** 2002-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210441

## Citation

> US National Institutes of Health, RePORTER application 10210441, Role of MAMs in stabilization and BACE1-mediated processing of palAPP. (5R01NS045860-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210441. Licensed CC0.

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