Yansheng Du - US grants

DESCRIPTION (provided by applicant): An increasing number of studies have suggested that inflammatory processes take part in the pathogenetic cascade of events that leads to Alzheimer's disease brain pathology. Induction of neuroinflammation involves the activation of astrocytes and microglial cells followed by the subsequent expression of a number of cytokines. Activated microglia producing proinflammatory cytokines such as interleukin-1 a (IL-1 alpha), interleukin-1 b (IL-1 Beta), and interleukin-6 (IL-6) have been found in areas surrounding extracellular amyloid plaques. Because there are no signs of acute infection in the brains of AD patients, chronic production of these cytokines may initiate a chain reaction that leads to enhanced release of neurotoxic cytokines, amyloid deposition, and subsequent neuritic amyloid plaque formation. Both elevated tissue levels of the IL-1 protein as well as increased number of activated IL-1 immunoreactive astrocytes found in AD brain suggest that IL-1 overexpression and thus amplification of a cytokine cycle may be a causative event to develop AD. Recently we and others reported that the IL-1A(-889) allele 2 is over-represented in patients with periodontitis as well as AD. We propose to continue and extend this study by confirming previously described interactions among the IL-1 polymorphisms in our cohort and investigating the incidence of the IL-1A(-889) allele 2 in cohorts of familial AD and African American AD patients compared to age/gender matched controls. We also propose to characterize potentially physiologically relevant changes (such as comparing the activities of promoters from allele 1 and allele 2 polymorphisms) by investigating the effects of this polymorphism may have on the regulation of IL-1 alpha. The overall goals of this proposal are: 1. To confirm whether or not IL-1A(-889), IL-1B(3953) and/or IL-1RA alone or together (interactions) increase the risk in our cohort as has been reported by other groups. Additionally, we will analyze relationships between IL-1A(-889) and the age of AD onset and rate of disease progression. 2. To investigate whether or not the IL-1A(-889) polymorphism confers an increase risk in cohorts of familial AD and African Americans. 3.To determine if lL-1A(-889), located in the promoter region of the IL-1A gene, results in increased activity under stimulatory conditions (LPS and ABeta) 4. To investigate whether or not there is a significant increase in CSF and plasma levels of the IL-1 a/b proteins in individuals homozygous for the IL-lA (-889) polymorphism (in both normal and patients with AD). Furthermore, we will investigate if whole blood from individuals homozygous for the IL-1A(-889) polymorphism responds to a greater extent than whole blood from a wild type homozygote individual under following stimulation by LPS or Ab for effects on IL-1 a/Beta secretion. We focus on IL-1A(-889) as this polymorphism conferring a risk to develop AD has been confirmed in our cohort. The significance of this work is that characterization of the IL-lA (-889) polymorphism and its relationship to AD as well as understanding its pathogenetic mechanism may aid in developing anti-inflammatory and anti-dementia drugs as well as targeting potential therapeutic treatments.

Abstract Amyloid-? protein (A?) 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 A?1-42, the CAA contains predominately A?1-40. The levels of SPs and CAA are inter-exchangeable by altering the ratio of A?1-42 and A?1-40. 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 A? 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 A?40/42 that favored CAA formation. Additionally, Pb-induced amyloid deposition and overexpression of transforming growth factor-? (TGF-?), 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-?1-induced expressions of PAI and fibronectin to disrupt the perivascular drainage and/or enhance binding of A? to cerebrovasculature. Additionally, human anti-A? 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-A? therapies for AD.