PROJECT SUMMARY
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 microhemorrhages 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.