Immune senescence in aged APP/PS1 mice.

Area of Science:

• Neuroimmunology
• Aging Research
• Alzheimer's Disease Pathogenesis

Background:

• Immune system deficits, encompassing both innate and adaptive immunity, are linked to Alzheimer's disease (AD) onset and progression.
• The precise pathobiological mechanisms connecting aging, immune dysfunction, and AD remain incompletely understood.

Purpose of the Study:

• To investigate the age-dependent changes in innate and adaptive immunity in the context of AD.
• To evaluate the functional integrity of regulatory T cells (Tregs) and their association with AD pathology in a mouse model.

Main Methods:

• Assessed Treg function, T cell frequencies, and microglial integrity in blood, lymphoid tissues, and hippocampus of transgenic (APP/PS1) and non-transgenic mice at various ages (4, 6, 12, 20 months).
• Utilized immune arrays on hippocampal tissues to analyze age-related molecular changes.
• Performed Ingenuity Pathway Analysis to identify dysregulated biological pathways.

Main Results:

• Transgenic APP/PS1 mice exhibited progressive impairment in Treg immunosuppressive function with age, with partial restoration observed at 20 months.
• Hippocampal tissue analysis revealed enrichment of inflammatory, oxidative stress, and cellular activation pathways, correlating with age and AD pathology.
• Key perturbed pathways included TREM1, Th1, NF-κB, IL-17, nitric oxide, acute phase, and T cell receptor signaling, with significant inflammation noted at 6 and 12 months.

Conclusions:

• Impaired Treg function, inflammation, and oxidative stress are associated with AD pathology.
• Age-related partial restoration of Treg function in older mice correlated with a reduced hippocampal inflammatory phenotype.
• Restoring Treg suppressive function presents a potential therapeutic strategy for Alzheimer's disease.