# Novel mechanisms for Alzheimer disease prevention and or treatment

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2021 · —

## Abstract

PROBLEM: Aging is the most important risk factor for Alzheimer's disease (AD), which represents the
most common cause of dementia in our country. The disease, for which there is no currently available
treatment, is becoming increasingly prevalent among our aging veteran population.
 PRELIMINARY DATA: Autophagy is an essential component of the cell degrading machinery. It helps
dispose of large toxic protein aggregates that form within the secretory pathway and in the cytosol.
Malfunction of autophagy and disruption of proteostasis contributes to the progression of many chronic
diseases. In addition, many chronic degenerative diseases are characterized by the aberrant accumulation
of toxic protein aggregates. Compelling data indicate that increased levels of autophagy can be beneficial in
mouse models of diseases characterized by increased accumulation of toxic protein aggregates, including
AD. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Nε-
lysine acetylation was initially thought to occur only in the cytoplasm and nucleus. However, in 2007 we
discovered that the endoplasmic reticulum (ER) is also able to acetylate newly-synthesized polypeptides.
Since then, we have successfully identified the entire biochemical machinery responsible for ER-acetylation
and generated relevant animal models. The machinery includes AT-1, which translocates acetyl-CoA from
the cytosol to the ER lumen, and ATase1/ATase2, two acetyltransferases that carry out the enzymatic
reaction within the ER lumen. We discovered that the ER acetylation machinery maintains the homeostatic
balance of two essential and intimately related functions of the ER: (i) “positive” selection of correctly folded
nascent polypeptides and (ii) tight regulation of autophagy/reticulophagy. Mice with reduced influx of acetyl-
CoA into the ER (AT-1S113R/+) display excessive induction of autophagy and a block of the secretory pathway
while mice with increased influx (AT-1 Tg and AT-1 sTg) display increased efficiency of the secretory
pathway and a block of normal reticulophagy. In both cases, lack of homeostatic balance leads to drastic
phenotypes. Relevant to this proposal is also the fact that a dysfunctional ER acetylation machinery has
been linked to aging and AD. Consistently, haploinsufficiency of AT-1 or biochemical inhibition of the
ATases was able to rescue the AD-like phenotype in the mouse.
 HYPOTHESIS: Our general hypothesis is that the ER acetylation machinery ensures protein
homeostasis. Deregulation of this cross-talk impacts both aging and AD.
 STUDY DESIGN: Specific Aim 1 will identify novel structure-based ATase1 and ATase2 inhibitors to
prevent AD. This Aim will take advantage of new structural information that we have collected on the
ATases and new structure-based inhibitors that we have recently identified. Relevant structural
biochemistry, in vitro and ex vivo analysis, and pre-formulation/formulation development of these novel
...

## Key facts

- **NIH application ID:** 10155429
- **Project number:** 5I01BX004202-03
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Luigi Puglielli
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155429

## Citation

> US National Institutes of Health, RePORTER application 10155429, Novel mechanisms for Alzheimer disease prevention and or treatment (5I01BX004202-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155429. Licensed CC0.

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