Year: 2009
Type: article
Abstract: Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allogeneic bone marrow cells. Here, we report a marked reduction in amyloid-β (Aβ) levels, β-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Aminergic Function in Brain Aging and Alzheimer's Disease, G39896335, Development of a new therapeutic strategy for Alzheimer's disease: Exploration of amyloid-beta inhibitors derived from foods and environment enrichment therapy., G5939010568, Florida Alzheimer's Disease Research, G6530347775, G7305574104, The Role of HIV-1 Tat in Alzheimer's Disease, Blocking TGF-Beta immune signaling as a therapeutic target for Alzheimer's diseas, Implication of HUCBC: a novel therapeutic strategy for Alzheimer's disease, CD40 Modulation of Abeta-Vaccine Immune Response, G9000167796, G9000355711
OpenAlex ID: W1994930383