Alzheimer's Disease and the Amyloid β Protein

Alzheimer’s disease (AD) is characterized by the deposition of amyloid in the extracellular compartment of the brain in the form of congophilic amyloid angiopathy (CAA) and amyloid plaques (APs). Intracellular neurofibrillary tangles (NFTs) (Terry, 1963) formed from the abnormally phosphorylated cytoskeletal protein tau are also seen (Lee et al., 1991). The identification of the amyloid b protein (Ab) in CAA and APs (Glenner and Wong, 1984; Masters et al., 1985) led to the cloning of the amyloid protein precursor (APP) (Kang et al., 1987). The discovery of familial AD (FAD) mutations in the APP gene (Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991; Naruse et al., 1991; Tanzi and Hyman, 1991) has supported the view that a defect in APP metabolism or function is directly involved in AD pathogenesis. The demonstration that mutations in the tau gene can lead to non-Alzheimer dementias with neurofibrillary pathology, lacking Ab plaques (reviewed by Spillantini and Goedert, 1998), has reinforced the view that the NFTs are a secondary phenomenon in the pathogenesis of AD. It has long been argued that the deposition of amyloid is an early step in AD pathogenesis (Masters et al., 1985; Hardy and Higgins, 1992; Masters and Beyreuther, 1993). The term amyloid refers to insoluble proteinaceous deposits that are congophilic and exhibit red– green birefringence in the presence of plane polarized light (Kisilevsky, 1994). Implicit in much of the research on the role of APP and Ab has been the assumption that deposits of amyloid are toxic to the brain (Jarrett and Lansbury, 1993) and that these deposits are the underlying cause of AD. The observation that Ab peptides when “aged” (incubated to form amyloid fibrils) become toxic to neurons in culture (Yankner et al., 1989; Frautschy et al., 1991; Kowall et al., 1991; Pike et al., 1991; Howlett et al., 1995) has further supported this view. The amyloid cascade hypothesis of AD, as formalized by Hardy and Higgins (1992), states that Ab “precipitates to form amyloid and, in turn, causes neurofibrillary tangles and cell death.” However, this hypothesis has been challenged (see, e.g., Davis and Chisholm, 1997; Hardy, 1997b). It has been argued that the deposition of amyloid does not correlate with dementia (Terry et al., 1991; Arriagada et al., 1992; Roses, 1994; Samuel et al., 1994; Braak and Braak, 1996), although the failure to observe a correlation may be related to the method by which AP load is measured (Cummings and Cotman, 1995). Whether amyloid deposits have a pathogenic role remains a controversial issue.