Immunotherapy for Alzheimer's disease

Strong evidence exists indicating that chronic neuroinflammation contributes to the progression of Alzheimer's disease (AD). A major focus of AD-associated research has been amyloid-beta (Abeta) protein deposits. Vaccination with Abeta stimulates phagocytosis of Abeta in transgenic mouse models of AD, leading to clearance of the deposits. Similar vaccination in humans with AD has, however, led to meningoencephalitis in some cases. The difference probably depends on the initial level of brain inflammation, which is much higher in bona fide AD in humans than in the transgenic mice. Because both pro- and anti-inflammatory activation of immune cells are possible, stimulating the phagocytic action of microglia while simultaneously stimulating anti-inflammatory activity might be beneficial in AD.     

Innate immunity, local inflammation, and degenerative disease

The brain lesions associated with Alzheimer's disease (AD), which are referred to as neurofibrillary tangles and senile plaques, are characterized by the presence of a broad spectrum of inflammatory mediators. Surprisingly, these mediators, which include complement proteins, inflammatory cytokines, prostaglandins, and acute phase reactants such as C-reactive protein and amyloid P, are produced by resident brain cells, including neurons. Although secondary to the fundamental pathology caused by the presence of tangles and plaques, there is strong evidence that inflammation exacerbates the neuronal loss. In particular, AD lesions show evidence of self-attack by the complement system--a part of the immune system that normally functions to rid the body of invading pathogens. However, the lesions are devoid of significant T cell infiltration, a hallmark of an inflammatory immune response, and antibodies. We define this phenomenon as autotoxicity to distinguish it from classical autoimmunity, in which the body raises antibodies to normal endogenous macromolecules. Locally produced inflammatory mediators have also been identified in atherosclerotic plaques, along with evidence of complement self-attack. As was previously shown for heart attacks, epidemiological evidence indicates that extended use of nonsteroidal anti-inflammatory drugs (NSAIDs) results in a reduced risk of AD. NSAIDs inhibit the production of prostaglandin inflammatory mediators, but powerful new therapeutic agents might be developed by targeting more critical inflammatory mechanisms, especially the complement system.