Work

The cholinergic system exerts opposing effects on memory at different stages of disease progression in Alzheimer's and Down syndrome model systems

Year: 2026

Type: article

Abstract: INTRODUCTION: The long-standing cholinergic hypothesis posits that cholinergic signaling is uniformly deficient in Alzheimer's disease (AD) and Down syndrome (DS). We tested the hypothesis that this deficiency occurs primarily late in disease, while early stages involve excessive cholinergic signaling, with distinct implications for memory. METHODS: Tg2576 (AD model; n = 38), Ts65Dn (DS model; n = 14), and wild-type (WT; n = 17) mice at young (3 to 4 months) and old (>14 months) ages received treatments to reduce cholinergic signaling (medial septum chemogenetic inhibition, muscarinic antagonist scopolamine) or enhance it (acetylcholinesterase inhibitor donepezil). Memory assessments used novel object recognition. RESULTS: Anticholinergic manipulations restored memory in young Tg2576 and Ts65Dn mice but impaired age-matched WT mice. Conversely, donepezil improved the memory of old Tg2576, Ts65Dn, and WT but not young Tg2576 and Ts65Dn animals. DISCUSSION: These findings refine and challenge the cholinergic hypothesis, revealing for the first time a functional shift from cholinergic hyperactivity driving early cognitive impairment to late-stage degeneration requiring enhancement.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.71154

Authors: Christos Panagiotis Lisgaras, Helen E. Scharfman

Institutions: Nathan Kline Institute for Psychiatric Research, New York State Office of Mental Health, New York University

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,200