Graduation Year

2004

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Pathology and Laboratory Medicine

Major Professor

Paul R. Sanberg.

Co-Major Professor

Jin Q. Cheng.

Keywords

amyloid, CD45, statin, phagocytosis, Aβ

Abstract

The work detailed in this dissertation has an overarching theme of modulating microglia activation in both in vivo and in vitro models relevant to AD. The premise is that understanding microglia function in this context may lead to a better understanding of AD pathogenesis and thus to effective therapeutic interventions. In chapter 3, we employ a well-defined model of microglia activation whereby the intraperitoneal delivery of LPS results in CNS microglia activation and TNF-α production. Having previously identified that CD45 signaling pathways antagonized microglia TNF-α production in vitro and given that immunotherapy with anti-CD45 antibodies are already in clinical trials for both the treatment of malignant disorders as well as for tolerance induction following organ transplants, we investigated whether microglial CD45 could be a relevant molecular target in the opposition of microglia activation in vivo.

Given that a number of epidemiological studies have shown an inverse correlation between the use of statins (a class of drugs that were initially described as specific inhibitors of cholesterol biosynthesis) and the incidence of Alzheimer's disease (Wolozin, 2000; Simon 2002; Zamrini, 2004); in chapter 4, we employed one of the most prescribed statins, lovastatin in our microglia activation paradigm. Interestingly, we show that statins only inhibit the enzyme HMG-CoA (the rate limiting step of cholesterol biosynthesis) but that they also display pleiotrophic effects including the inhibition of CD40 expression. Given the role of CD40 in microglia activation and its potential role in AD pathogenesis, we investigated whether lovastatin's protection in AD might be derived from effects on microglia function as governed by the CD40 pathway.

In chapter 5, we provide evident for a model of microglia activation that addresses some of the current controversies concerning the role of microglia cells in AD pathogenesis. The model suggests that microglia cells exist in a number of distinct activation states, in one such state that we denote the "phagocytic state"; microglia function to clear cellular debris or foreign invaders or in the case of AD to remove β-amyloid/Aβ peptides. However, in response to certain co-stimuli (i.e. CD40 activation) these microglia take the form of an "antigen presenting cell" (APC) whereby they lose their phagocytic capacity in lieu of cytokine production and thus potential contributing to AD pathogenesis.

Share

COinS