Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice
- 1Dartmouth College
Abstract
Although prenatal alcohol exposure (PAE) has been proposed as an early- life risk factor for Alzheimer's disease and related dementias (AD/ADRD), the mechanistic underpinnings are underexplored. Mutations in the Presenilin genes contribute to AD/ADRD, with Presenilin 1 acting as the catalytic subunit of the gamma-secretase complex responsible for cleaving Notch and amyloid precursor protein (APP). We hypothesized that PAE disrupts gamma-secretase activity during brain development, which persists and is associated with behavioral deficits later in life. Pregnant wild-type B6129 and 3xTg-AD mice were fed an ethanol-containing liquid diet during gestational days 13-15. From birth to adulthood, PAE increased APP C-terminal fragments and Notch intracellular domain (NICD) levels in cortical lysates. These changes were accompanied by impaired hippocampal-dependent learning and memory in wild-type mice at 3 and 6 months of age and exacerbated behavioral deficits in 4-month-old 3xTg-AD mice. Our findings provide the first mechanistic insight linking PAE to AD/ADRD vulnerability.
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BibTeX
@misc{montenegro2026prenatal,
title = {{Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice}},
author = {P. C. Montenegro and R. Kim and M. Zedek and M. Chicas and P. W. L. Yeh and H. H. Yeh},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.11.731622},
url = {https://www.biorxiv.org/content/10.64898/2026.06.11.731622v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Prenatal Alcohol Exposure Disrupts γ-Secretase Activity and Impairs Learning and Memory in Wild-Type and 3xTg-AD Mice
AU - P. C. Montenegro
AU - R. Kim
AU - M. Zedek
AU - M. Chicas
AU - P. W. L. Yeh
AU - H. H. Yeh
PY - 2026
DA - 2026/06/11
PB - bioRxiv
DO - 10.64898/2026.06.11.731622
UR - https://www.biorxiv.org/content/10.64898/2026.06.11.731622v2
AB - Although prenatal alcohol exposure (PAE) has been proposed as an early- life risk factor for Alzheimer's disease and related dementias (AD/ADRD), the mechanistic underpinnings are underexplored. Mutations in the Presenilin genes contribute to AD/ADRD, with Presenilin 1 acting as the catalytic subunit of the gamma-secretase complex responsible for cleaving Notch and amyloid precursor protein (APP). We hypothesized that PAE disrupts gamma-secretase activity during brain development, which persists and is associated with behavioral deficits later in life. Pregnant wild-type B6129 and 3xTg-AD mice were fed an ethanol-containing liquid diet during gestational days 13-15. From birth to adulthood, PAE increased APP C-terminal fragments and Notch intracellular domain (NICD) levels in cortical lysates. These changes were accompanied by impaired hippocampal-dependent learning and memory in wild-type mice at 3 and 6 months of age and exacerbated behavioral deficits in 4-month-old 3xTg-AD mice. Our findings provide the first mechanistic insight linking PAE to AD/ADRD vulnerability.
ER -