Year: 2026
Type: preprint
Abstract: Background Individuals with Down syndrome (DS) are at exceptionally high risk of developing early-onset Alzheimer’s disease (AD) and exhibit age-associated cognitive decline and chronic immune dysregulation. Although adaptive immunity can exert both protective and detrimental effects in neurodegenerative disorders, its contribution to AD-related pathology in DS remains poorly understood. Methods We characterized amyloid pathology, behavioral performance, and adaptive immune alterations in aged Dp1Tyb mice, a mouse model of DS. We further evaluated the effects of B-cell depletion using anti-CD20 antibody and active immunization against murine amyloid-beta (mAβ). Statistical analyses included t-tests, analysis of variance (ANOVA), and linear mixed-effects models, as appropriate. Results Aged Dp1Tyb mice exhibited increased soluble hippocampal and cortical mAβ 40, reduced mAβ 42/40 ratios, short- and long-term spatial memory impairments, altered exploratory behavior, and impaired motor performance. These phenotypes were accompanied by systemic adaptive immune dysregulation, characterized by reduced mature B-cell populations and increased T-cell representation across peripheral and central nervous system (CNS)-associated immune compartments. B-cell depletion in male mice reduced soluble mAβ 40 levels and selectively improved short-term spatial memory while inducing tissue-dependent increases in CD4 + and CD8 + T-cell abundance. Active mAβ immunization in female mice reduced soluble mAβ 40 levels, partially normalized hippocampal microglial morphology, and was associated with improved short-term spatial memory-related performance. Conclusions These findings support adaptive immunity as a modifiable component of AD-related pathology in DS. Notably, B-cell depletion and active mAβ immunization converged on reduced mAβ 40 and favorable short-term memory-related outcomes despite distinct effects on adaptive immune and microglial phenotypes, suggesting that multiple immune pathways can influence AD-related outcomes in DS. These findings are limited to a preclinical mouse model, and the mechanisms underlying the observed effects require further investigation.
Source: Research Square
Institution: Bar-Ilan University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225195663