Four recent large genome-wide association studies in late- onset AD have documented, in addition to the ApoE ??4 allele genotype, nine novel loci as risk factors for developing AD, including genes encoding proteins implicated in inflammatory processes (clusterin selleck chemicals llc (CLU, chromosome 8, rs11136000) and complement receptor-1 (CR1, chromosome 1, rs6656401)) [26,27]. Clusterin is a multifunctional protein involved in both complement attack inhibition and cholesterol metabolism, and complement receptor-1 is the receptor for the cleavage products of complement proteins 3 and 4, which are present in plaques. All nine new genes map onto three pathways leading to late-onset AD: immune system function, cholesterol metabolism, and synaptic dysfunction [28].

Diffuse plaques, the initial pathological lesion in AD, contain a limited number of proteins, which are now all linked with a genetic risk for AD, with ACT as the exception. Abnormalities in the generation of A?? are considered as the causal factor for the familial forms of early-onset AD, whereas poly-morphisms of the genes encoding for ApoE, clusterin and complement proteins are the genetic risk factors for late-onset AD. Genome-wide association studies for late-onset AD have not revealed genetic factors related to A?? generation but instead to the A??-associated proteins already present in the initial neuropathological lesion. Taken together, the data on the protein composition of diffuse plaques and the recent genetic findings strongly suggest an interaction between A??, cholesterol metabolism and complement activation in the initial steps of the pathological cascade in AD.

Glia and pro-inflammatory cytokines Fibrillar A?? plaques are associated with clustering of activated microglia and astrocytes. These glial cells play an important role in innate immunity and express a family of receptors, the Toll-like receptors (TLRs), as a first line of defense responsible for recognizing specific pathogen-associated molecular patterns like fibrillar A??. TLRs and CD14, both innate immunity receptors, mediate activation of transcription factors such as NF-??B and subsequently the production of inflammatory cyto-kines Batimastat [29]. Accumulating evidence indicates that CD14 and TLR4 are essential in the interaction of glial cells with A?? for the production of pro-inflammatory cytokines [30-32].

In vitro studies have shown that A?? fibrils interact with the TLR2/4 accessory protein CD14 and both TLR2 and TLR4 mediate A??-induced production of TNF-?? in human monocytes. Mouse microglia show in vitro increased ingestion of A?? after activation of TLR2, TLR4 or TLR9. Stimulation of the innate immune system via TLR9 is reported to be highly selleck catalog effective at reducing the parenchymal and vascular amyloid burden without apparent toxicity in a transgenic AD mouse model [33].