Multiparity exacerbates Aβ accumulation and promotes cellular senescence in a mouse model of amyloidosis

Women have nearly twice the lifetime risk of Alzheimer’s disease (AD) as men. Hormonal and reproductive factors have been implicated; however, the role of parity, a female-specific experience, remains unknown. While epidemiological data suggest that high parity may increase the risk of dementia, the underlying biological mechanisms are unclear. We investigated the impact of multiparity on AD pathology using 2-month-old female 5xFAD mice. Mice were assigned to a nulliparous (0x) or multiparous (4x) (four consecutive gestation cycles) group. Brain tissues were analyzed at 6.4 months of age for Aβ pathology, neuroinflammation, synaptic markers, and senescence. Proteomic profiling and in vitro hormone treatment identified the key mediators. The role of voluntary running was assessed in a separate cohort of nulliparous mice. Multiparous 5xFAD mice showed increased Aβ plaque burden, elevated BACE1 expression, synaptic loss, and activated senescence pathways compared to nulliparous controls. Proteomic analysis revealed sustained upregulation of the transcription factor FOSB. FOSB was found to drive BACE1 expression and Aβ production. In vitro co-treatment with estradiol and progesterone increased FOSB and BACE1 levels, supporting the presence of a hormone-responsive regulatory link. In nulliparous female 5xFAD mice, voluntary running from 2 to 6 months of age reduced Aβ deposition, fewer FOSB+ neurons, and microglial activation compared with those in the sedentary controls. Our findings identified the FOSB/BACE1 signaling axis as a link between reproductive history and AD pathology. Multiparity accelerates amyloid pathology and brain aging in female 5xFAD mice, mechanistically linked to hormone-driven FOSB upregulation. Physical activity downregulates this pathway in nulliparous animals. Whether exercise can mitigate parity-associated pathology remains to be investigated in multiparous animal models.