# Decreased Length of Locus Coeruleus Norepinephrine Axons and Increased Amyloid Beta Pathology in Male APP/PS1 Mice During Protracted Abstinence From Alcohol

## TL;DR

Male mice with Alzheimer's disease traits show reduced norepinephrine axon length and increased amyloid beta after alcohol abstinence, but effects are less severe than in females.

## Contribution

The study reveals sex-specific effects of alcohol abstinence on amyloid pathology and norepinephrine axon length in a mouse model of Alzheimer's.

## Key findings

- Male APP/PS1 mice showed decreased LC norepinephrine axon length after alcohol abstinence.
- Alcohol-exposed male APP/PS1 mice had increased amyloid beta pathology.
- The number of LC norepinephrine neurons remained unchanged in male mice, unlike in females.

## Abstract

Alzheimer’s disease (AD) is the leading cause of dementia and evidence suggests that alcohol, the most commonly used addictive substance, may increase AD risk. Locus coeruleus (LC) neurons are the primary source of norepinephrine in the brain and these neurons degenerate early in AD. In rodent models, lesioning the LC increases amyloid beta (Aβ) pathology suggesting that LC integrity and norepinephrine signaling obstruct Aβ pathogenesis. We recently reported a decrease in the number of LC norepinephrine neurons and increased Aβ pathology when measured after protracted abstinence from chronic intermittent alcohol consumption in female APP/PS1 mice. Clinically, female subjects are at a higher risk for AD; additionally, female mice consume more alcohol than male mice making it unclear as to whether alcohol consumption would produce similar adverse outcomes in male subjects. To address this gap, male APP/PS1 and non-transgenic mice underwent chronic intermittent access (IA) to alcohol followed by protracted abstinence with water drinking controls run in parallel, consistent with our prior study. In contrast to our previous results with female mice, the number of LC norepinephrine neurons was unchanged in male APP/PS1 mice that had IA to alcohol; however, the length of LC axons was decreased and Aβ pathology was increased in male APP/PS1 mice that consumed alcohol. These data demonstrate that alcohol consumption during early adulthood results in negative consequences in male APP/PS1 mice, although the effect may not be as severe as previously observed in female mice.