Monday, May 16, 2022
5/16/2022
Abstract Amyloid-ß protein (Aß) is not only present in brain parenchyma in the form of senile plaques (SPs), but also exists in the brain capillary vessels; the latter is defined as the cerebral amyloid angiopathy (CAA), which is a recognized prominent pathological feature of Alzheimer disease (AD). CAA occurs sporadically, being observed in approximately 85%–95% of AD patients. The advanced CAA leads to spontaneous lobar hemorrhages and ischemic lesions/infarcts. In contrast to SPs that are largely composed of Aß1-42, the CAA contains predominately Aß1-40. The levels of SPs and CAA are inter-exchangeable by altering the ratio of Aß1-42 and Aß1-40. Human apoEe4, a sporadic AD risk factor, also facilitates the formation of CAA over SPs. CAA-mediated hemorrhage is closely associated with activated microglial cells and astrocytes11. Recently, many Aß immunotherapies were shown to increase cerebral micro- hemorrhages associated with amyloid-laden vessels, although not all immunotherapies are alike. It appears there are distinct molecular mechanisms underlying SPs- and CAA-mediated AD development. Currently, Pb remains to be a major public health concern. We showed Pb exposure elevated and kept high ratios of brain Aß40/42 that favored CAA formation. Additionally, Pb-induced amyloid deposition and overexpression of transforming growth factor-ß (TGF-ß), a risk factor for CAA formation, were found in leptomeninges. We therefore propose to test whether Pb in two different APP transgenic mouse lines is able to induce inflammation- associated CAA that leads to cerebral microhemorrhages by using USPIO MRI/18F-AV45 PET and immunohistochemistry (IHC), and the Pb-induced CAA results from TGF-ß1-induced expressions of PAI and fibronectin to disrupt the perivascular drainage and/or enhance binding of Aß to cerebrovasculature. Additionally, human anti-Aß antibodies and TM5275, a specific inhibitor of PAI-1, will be used to further test our hypothesis. We believe that our hypothesis will reveal, for the first time in literature, the CAA, independent of SPs, as the responsible mechanism for Pb-mediated AD pathogenesis/development and this study will provide the opportunity to develop the early diagnostic method and effective anti-Aß therapies for AD.
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