# Preventing Alzheimer's Disease with Designer Lipids

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $231,750

## Abstract

PROJECT SUMMARY
Approximately 5.4 million people in the USA are afflicted with Alzheimer's Disease (AD), causing a marked
cognitive decline and a doubling of the mortality rate for afflicted patients aged 70-80. AD (combined with simi-
lar dementias) currently costs the USA healthcare system ~$277 billion a year. That cost is predicted to in-
crease significantly as the population ages. Preventing and clearing amyloid beta (Aβ) plaque is key to long-
term, effective treatment of AD. In 2013, administration of a chemically-derived bacterial product, monophos-
phoryl lipid A (MPLA), a non-toxic derivative of the lipid A region of lipopolysaccharide (LPS), prevented the
onset of AD-like symptoms in a mouse model, demonstrating a relatively inexpensive and effective route for
AD prevention through weak Toll-like receptor 4 (TLR4) agonism. However, there are several problems with
MPLA, the most important being the structural heterogeneity and inconsistency of the product. In contrast, we
designed and expressed an MPLA-like functional homolog (lipooligosaccharide, LOS) in live bacterial strains
that yield a more homogeneous product and are inexpensive to produce and purify. We have produced and
tested a structurally-engineered MPLA-like LOS (Attenuated Lipid A Therapeutic, ALT), that is protec-
tive from learning impairment in an AD-prone mouse model when given as a weekly low-dose injection.
The underlying pathophysiology of AD likely starts very early (well before presentation as dementia) and it is
still poorly understood, despite decades of effort. However, there are numerous reports suggesting that AD is
the consequence of chronic inflammation in the brain, through persistent, strong stimulation of pattern recogni-
tion receptors (PRR). Ligands for PRRs are numerous; specifically for TLR4 they include canonical LPS (also
LOS and lipid A), but also several non-canonical molecules including Aβ peptide. Thus, competition at TLR4
may prevent inflammation associated with amyloid deposition by displacing more pro-inflammatory agonists.
Further, microglial cells weakly activated through TLR4 were shown to have increased phagocytic activity in-
cluding clearance of Aβ. We have demonstrated that ALT protects from AD-like learning impairment and this
proposal will address protection in other early onset AD mouse models. Further, since ALT is produced from a
live bacterial strain, we will investigate the use of the live strain as a potential probiotic therapy rather than a
weekly injection of extracted LOS. This proposal aims to develop a live bacterial probiotic to prevent AD. This
is an inexpensive and potentially highly impactful approach to AD prevention and therapy.

## Key facts

- **NIH application ID:** 10475150
- **Project number:** 5R21AG074331-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Alison J Scott
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,750
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475150

## Citation

> US National Institutes of Health, RePORTER application 10475150, Preventing Alzheimer's Disease with Designer Lipids (5R21AG074331-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475150. Licensed CC0.

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