The Early Involvement of the Innate Immunity in the Pathogenesis of Lateonset Alzheimers Disease: Neuropathological, Epidemiological and Genetic Evidence

P.      Eikelenboom; R.      Veerhuis; E.      van Exel; J.      J.M. Hoozemans; A.      J.M. Rozemuller; W.      A. van Gool

doi:10.2174/156720511795256080

Abstract

The idea that an inflammatory process is involved in Alzheimers disease (AD) was proposed already hundred years ago but only the past twenty years inflammation-related proteins have been identified within plaques. A number of acute-phase proteins colocalize with the extracellular amyloid fibrils, the so called Aβ-associated proteins. Activated microglia and astrocytes surrounding amyloid deposits express receptors of innate immunity and secrete pro-inflammatory cytokines. In this paper we review the evidence for involvement of innate immunity in the early stages of the pathological cascade of AD. Diffuse plaques, the initial neuropathological lesion in the cerebral neocortex, contain next to Aβ also apolipoprotein E, clusterin, α1-antichymotrypsin and activated complement proteins. Interestingly, genetic studies have shown gene-loci to be associated with AD for all these proteins, except α1-antichymotrpsin. Fibrillar Aβ can, through stimulation of toll-like receptors and CD-14 on glial cells, activate pathways for increased production of pro-inflammatory cytokines. This pathway, inducing production of proinflammatory cytokines, is under genetic control. The finding that the responsiveness of the innate immunity is higher in offspring with a parental history of late-onset AD indicates heritable traits for AD that are related to inflammatory processes. Prospective epidemiological studies which report that higher serum levels of certain acute-phase proteins are associated with cognitive decline or dementia provide additional evidence for the early involvement of inflammation in AD pathogenesis. The reviewed neuropathological, epidemiological and genetic findings show evidence for involvement of the innate-immunity in the early stages of pathological cascade as well as for the hypothesis that the innate immunity contributes to the etiology of late-onset AD.

Keywords: Alzheimer's disease, Aβ-associated proteins, innate immunity, neuroinflammation, microglia, toll-like receptors, cytokines, inflammaging, minocycline