Saturday, January 25, 2025
1/25/2025
Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and a damaged cerebral vasculature. Moreover, the majority of patients with dementia present with both AD and vascular pathologies. Circulatory deficiencies could therefore play an important role in this disease. Cerebral amyloid angiopathy (CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD and is observed in more than 80% of AD patients. Post-mortem pathological examination of patients' brains with CAA shows perivascular microhemorrhage, microinfarcts, and capillary occlusion. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. In addition, a definitive diagnosis of CAA requires autopsy as there is no clear biomarker for CAA. There are rare familiar forms of CAA, called hereditary cerebral amyloid angiopathy (HCAA), in which patients display exaggerated CAA pathology and a severe clinical course of strokes as well as suffering from early onset neurological dysfunction, dementia, and ultimately death. The majority of HCAA occurrences coincide with mutations within the gene for the β-amyloid precursor protein (APP). While most APP mutations elevate total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to HCAA causes an increase in vascular deposits of Aβ. Since patients afflicted by HCAA mutations have severe cerebrovascular deficits along with massive CAA, HCAA is an ideal disease to examine the pathogenic mechanisms of CAA. Increasing evidence suggests that fibrinogen, a major component of blood clots, contributes heavily to the cerebrovascular risk in AD. Fibrinogen binds to Aβ with high affinity, and this interaction increases the incidence of abnormal fibrin clots, CAA, inflammation, and cerebrovascular damage. Our preliminary results indicate that HCAA mutations highly increase Aβ’s binding affinity for fibrinogen and induce more severely altered fibrin clot structure than wild-type (WT) Aβ. Based on these findings, we hypothesize that HCAA mutations increase Aβ’s binding affinity for fibrinogen, which subsequently induces more severely altered fibrin clotting, increases vascular fibrin and Aβ deposition, and exacerbates inflammation and cerebrovascular damage. By investigating our hypothesis in a mouse model of HCAA, as well as antemortem CSF and postmortem brain tissue of HCAA patients, we aim to understand the molecular mechanism underlying increased CAA and cerebrovascular abnormalities in HCAA. If our proposed experiments are successful, the results will help us to better understand the pathogenic mechanism underlying the vascular contribution of CAA in both AD and HCAA patients. In addition, our research will provide a novel CSF biomarker for CAA. Furthermore, these findings may accelerate the discovery of tractable therapeutic methods for vascular pathology in AD.
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