Molecular pathology of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the presence of large numbers of senile plaques, neurofibrillary tangles and neuroinflammatory cells. Evidence from genetic studies suggests that the formulation of these plaques is fundamental to the development of AD and that plaques have a central role to play in the instigation of the other pathologies found in AD. To date, four genes have been identified as contributing to the genetic aetiology of AD; amyloid precursor protein, presenilin 1, presenilin 2 and apolipoprotein E. All of these genes have been shown to have a role in the development of senile plaques with some shown to directly facilitate the cleavage of amyloid, the core component of senile plaques, from its parent molecule, amyloid precursor protein. An understanding of the genetic aetiology of AD has led directly to the development of drugs that interfere with the cleavage of intact amyloid from amyloid precursor protein. The aggregation of amyloid molecules is thought to have an important role in the development of tangles and the activation of inflammatory cells. Compounds that disrupt the aggregation of amyloid plaques are already undergoing clinical trials. In addition, studies have shown that amyloid plaques can be removed by active immunization. The formulation of neurofibrillary tangles may be facilitated by activation of several kinases, including GSK-3. More recently, it has been shown that these kinases can be inhibited by drugs including lithium, and so these drugs have now been identified as possible therapeutic agents.