Immunological aspects of Alzheimer's disease - Therapeutic implications

Alzheimer's disease (AD) is a chronic neurodegenerative disease causing pro gressive impairment of memory and cognitive function. The amyloid cascade h ypothesis suggests that mismetabolism of the beta -amyloid (A beta) precurs or protein (APP) followed by subsequent formation of non-fibrillar and fibr illar A beta deposits leads to glial activation and eventually to neurotoxi city, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflamm atory proteins have been identified as being associated with neuritic plaqu es and in glial cells surrounding these plaques. Second. certain polymorphi sms of acute-phase proteins and cytokines associated with AD plaques increa se the risk or predispose for earlier onset of developing AD. Third, epidem iological studies indicate that anti-inflammatory drugs can retard the deve lopment of AD. Several steps in the pathological cascade of AD have been id entified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell ty pe is closely involved in AD pathology through secretion of neurotoxic subs tances and by modulating a positive feedback loop of the inflammatory mecha nism that may be involved in the pathological cascade in AD. On the basis o f studies in APP transgenic mice, immunisation with A beta was recently sug gested as a novel immunological approach for the treatment of AD. Immunisat ion elicits A beta -specific antibodies that could affect several early ste ps of the amyloid-driven cascade. Antibodies could prevent A beta from aggr egating into fibrils and accelerate clearance of A beta by stimulating its removal by microglial cells. This review outlines the pathological and gene tic evidence that an inflammatory mechanism is involved in AD and the thera peutic approaches based on inhibition or mediation of inflammation.