# Acyl chain remodeling and regional lipid dysregulation in Alzheimer's disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $382,302

## Abstract

Accumulating data from human and mouse support the hypothesis that system level lipid disregulation is an
early and critical factor in etiology and progression of Alzheimer's disease (AD). The explosion of 'omics
methods in the past decade has resulted in a proliferation of various studies and data sets that interrogate
specific regions of the brain. Using Imaging Mass Spectrometry (IMS), our preliminary studies have found
regionally differential lipid composition in coronal sections from wild type mouse brain and a mouse model of
Alzheimer's disease over expressing the amyloid precursor protein (APP) transgene. This regional lipid
disregulation requires system-wide interrogation of lipid homeostasis which can singularly be accomplished
with lididomics. A candidate based screen of lipid modifying enzymes in mouse embryonic stem cells for
resistance to Aβ-triggered synapse loss, identified multiple metabolic enzymes which may be responsible for
exit of polyunsaturated fatty acids (PUFA), specifically docosahexaenoic acid (DHA) from an acyl chain
remodeling pathway, the Land's cycle. The Land's cycle has recently been identified to be dysfunctional in two
animal models of AD. In the human context, DHA transport into the brain is aberrant by age 30, in carriers of a
variant of apolipoprotein E (ApoE4) strongly associated with AD risk. Synthesis of these results with multiple
hits from GWAS implicating lipid metabolism and transport, strongly support system-wide dyshomeostatis of
acyl chain composition in the brain. However, the reports of regionally defined lipid composition are currently
limited. We propose to test the hypothesis that acyl chain composition among multiple lipid classes is severely
disregulated in brain regions known to be susceptible in AD including hippocampus and entorhynal cortex.
Using IMS we will interrogate the lipid composition of mouse models of AD, Tg2576 and targeted replacement
APOE mice as well as human brain tissue. We will then test the hypothesis that DHA accretion is a critical
modifier of AD associated behavioral deficits and pathology in mouse models using knock-out lines of acyl-
CoA synthetase 6 (Acsl6), a key mediator of DHA enrichment in the brain. We will generate new strains of
Tg2576 and TRAPOE4 lacking Acsl6 and overexpressing Acsl6 to determine both necessity and sufficiency of
DHA brain accretion for AD associated deficits. Finally, we will integrate and assemble our data into a
publically available lipid brain atlas. These studies have potential to synthesize accumulating lipidomics data in
aging and neurodegenerative disease. The use of spatial lipidomics at scale in the brain has not been yet be
comprehensively accomplished, and is required for clear understanding of the basic metabolic pathways thus
uncovering connectivity and functionality in the brain. Completion of these studies will represent compelling
evidence for the critical nature of lipid composition in basic biology of AD and lead to new s...

## Key facts

- **NIH application ID:** 10863960
- **Project number:** 5R01AG072794-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Laura Beth Johnson McIntire
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,302
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863960

## Citation

> US National Institutes of Health, RePORTER application 10863960, Acyl chain remodeling and regional lipid dysregulation in Alzheimer's disease (5R01AG072794-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10863960. Licensed CC0.

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