The objective of this Project is to address the idea that glial inflammatory changes associated with over-expression of glia-derived cytokines, in particular interleukin-1 (IL-1) and S100beta, are primer movers in a cascade of events that leads to neuronal cell injury and death in the early pathogenesis of Alzheimer's disease (AD). These cytokine-driven cascades of neuronal dysfunctions include early over-expression of the amyloid-beta (Abeta), precursor protein (betaAPP), accumulation of neurofibrillary tangles (NFTs), over-growth of betaAPP over-expressing neurites, appearance of neuropil threads, and eventually cell death. Chronic activation of these cytokine-driven neurodegenerative cascades can, in turn, promote further over-expression of IL-1 and, in this way, become self propagating. We will use molecular techniques to define sequential relationships, genetic modulation, and mechanistic processes in such a self-propagating cycle. Our 3 aims 2ill 1) define the sequential relationship of glial inflammation to neuronal cell injury (as evidenced by betaAPP, over-expression and neurofibrillary tangle formation in neurons, neurites, and in neuropil threads, as well as by synaptic changes) and neuronal cell death (as evidenced by TUNEL positivity) in early Braak and Braak stages (I-IV) for comparison to later stages (V-VI), and with AD. These will be correlated with the incidences of i) activated microglia over-expressing IL-1, ii) activated astrocytes over-expressing S100beta, iii) Abeta plaques of different types, and iv) NFTs at different stages of formation; 2) define the modulating effects of IL-1 genotype on glial inflammation and on neuronal cell injury and death in AD and in conditions predisposing to AD or to accelerated appearance of AD-type senile changes. For this, we will use material from patients at Braak and Braak stages I-IV of neurofibrillary changes and from patients with Down's syndrome of epilepsy; and 3) more directly assess the role of glial activation and over-expression of glia-derived cytokines in genetically modified animal models, including mice with a mutated human betaAPP transgene, mice over-expressing or not expressing S100beta, mice over-expressing IL-1, and crossbred offspring of these mice. In these animals,. We will also assess the local and remote effect of exogenous cytokines in vivo, using intracerebral implants of timed-release pellets containing specific glial cytokines or other cytokine cycle molecules. Successful completion of these aims will provide information regarding the progression of neuropathological changes in AD and will highlight targets for therapeutic strategies to slow the clinical progression of AD.
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