The Immunopathology of Alzheimer's Disease and Some Related Disorders

Abstract

Current evidence clearly indicates that elements of the immune system are involved in the pathogenesis of the principal lesions characterizing Alzheimer's disease (AD). Findings are in accord with features associated with both the innate and adaptive immune mechanisms involved in a predominantly local inflammatory response within the parenchyma. Many of the features are unique to AD, presumably related to the unusual properties of beta amyloid protein. Remarkably, the brain holds the capacity to produce almost all the immune system mediators which largely seem to be generated by glia comprising both astrocytes and microglia. While a variety of humoral mediators including classical acute phase proteins (and serpins) are increased and released, the complement seems most intrinsically involved. The cellular response is elaborated by microglia which seem the main immunocompetent cells partaking in the response. These appear to function as pluripotent macrophages expressing both classes of MHC antigens. Further characterization of this interesting response to cerebral amyloidosis will be challenging.

Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain

“…Cellular and molecular analyses revealed that synaptic damage, loss of calbindin-IR neurons, microglial activation, and the level of cerebral acute-phase response corresponded with the differential avoidance learning observed in heterozygous and homozygous GFAP-IL6 mice. Activation of microglia and up-regulation of cerebral acutephase response gene expression are implicated in the pathogenesis of human neurodegenerative disorders such as HIV encephalitis and Alzheimer disease (20)(21)(22). The contribution of these altered states to the development of neurodegeneration is not known, although it has been speculated that in the case of microglial activation in particular, these cells may elaborate a variety of potentially neurotoxic factors (20)(21)(22)(23).…”

Platelet activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity

“…In vivo and in vitro models of cell death differ in that neurons subjected to excitotoxic challenge in vivo are coincidentally exposed to high concentrations of proinflammatory agents. This exposure is also implicated in a number of clinical neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, ischemia, and epilepsy (Kalaria, 1993;Giulian et al, 1994;Majno and Joris, 1995;Steinberg et al, 1996). What role do proinflammatory agents play in mediating excitotoxic cell loss?…”

Neuroautoimmunity: Pathogenic Implications for Alzheimer’s Disease

“…As reviewed by Kalaria [32], autopsies also contained complement proteins (Clq, C3d, C4d, C5b, C l, C9, C4bp, CD59). mRNA for complement components (Clq, C3, C4, C4bp, and CD59), cellular adhe sion molecules (ICAM-1 and PECAM).…”

“…The link between AD and in flammation is based on: retrospective studies of rheumatoid arthritis and frequency of se nile dementia of the AD type [31 ]; response to the anti-inflammatory drug indomethacin [34]; inverse relationship between anti-in flammatory treatments and AD [35,36], Typ ical signs of inflammation such as edema and neutrophil invasion are not found in the post mortem brains of AD. However, several im mune markers have been localized: MHC class I and II antigens, leukocyte antigens, IL-2 and IL-2 receptor, complement proteins and their receptors, ICAM, and TNF [32], The topic of inflammation in AD has stim ulated considerable interest amongst re searchers particularly because of pAP-induced activation of the complement in vitro [37], However, inconsistent with AD neuro pathology, it does not explain disease specific ity or regional specificity in the affected or gan. Anti-inflammatory treatments for rheu matoid arthritis also elicit immunomodulato ry effects, for instance ACTH and prednisone are well known immunosuppressants whereas indomethacin augments NK cell function in immunosuppressed host [38].…”