Early dorsal hippocampal catecholaminergic vulnerability is associated with sex-specific susceptibility to proactive interference in APP/PS1 mice.

Abstract

Interference is a major contributor to early memory decline in Alzheimer's disease (AD), yet standard assays often fail to detect vulnerability at pre-plaque stages; to address this, male and female 2-month-old APP/PS1 and wild-type mice were assessed using a proactive-interference-modified novel object recognition (PI-NOR) paradigm, alongside quantitative analysis of tyrosine hydroxylase-positive (TH⁺) catecholaminergic axon terminals across dorsal and ventral hippocampal subregions. Despite typically intact recognition at this age, PI selectively impaired recognition memory in male APP/PS1 mice, while females retained stable performance, revealing a sex-specific susceptibility to interference. This behavioral deficit in males was paralleled by a reduction in TH⁺ catecholaminergic terminals confined to the dorsal hippocampus, with no comparable loss observed in females. Augmenting β-adrenergic signaling with chronic isoproterenol administration restored recognition performance in male APP/PS1 mice under PI conditions without altering baseline NOR. These findings establish PI as a sensitive probe of latent recognition instability and indicate that reduced dorsal hippocampal catecholaminergic input is associated with interference-related vulnerability in male APP/PS1 mice.