Induction of neurodegeneration in the hippocampus of senescence-accelerated mouse-prone 8 (SAMP8) mice by blood-brain barrier-crossing serum amyloid P component

Aging is a major risk factor for neurodegeneration. However, the mechanisms by which age-related disruptions in brain homeostasis induce neurodegeneration remain controversial. To clarify this, we analyzed how age-related changes in blood components induce blood-brain barrier (BBB) structure disruption and neurodegeneration using 6-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice. First, we found that 6-month-old SAMP8 mice showed a decline in learning and memory abilities. We used the senescence-associated β-galactosidase marker to visualize which brain regions were responsible for the behavioral change, showing that the hippocampus had a drastic accumulation of senescence-associated β-galactosidase in SAMP8 mice. Next, we performed multi-omics profiling, which demonstrated that SAMP8 mice showed remarkable changes in the expression of BBB maintenance and immune system-related genes at the early stage of aging. Consistent with these results, the structure of occludin-positive tight junctions in the BBB and the number of microglia were altered in the hippocampus of SAMP8 mice. In addition, SAMP8 mice showed an increase in apoptotic hippocampal neurons and a decrease in synaptic density in mossy fibers, leading to impaired learning and memory. Interestingly, proteomic and immunostaining analyses revealed that one of the blood components, the serum amyloid P component (SAP), translocates to the hippocampus while passing through the BBB in SAMP8 mice. In addition, SAP increased BBB permeability by altering the structure of occludin-positive tight junctions, as shown via in vitro analyses. Furthermore, SAP can lead to neuronal cell death and a decline in synaptic density. Overall, our results reveal a previously unrecognized mechanism by which aging induces neuronal death and impairs learning abilities. These results represent an important conceptual advance in that the increase in the serum component SAP disrupts BBB homeostasis, and consequently, SAP leakage into the brain parenchyma leads to neurodegeneration during aging in SAMP8 mice.