Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease.

Abstract

One of the most rewarding moments in science arises when research on seemingly disparate processes begins to reveal a broad, common principle. Such a confluence has occurred recently in the study of several etiologically unrelated brain diseases that display distinct symptoms and pathologies. In a growing number of neurodegenerative disorders, the accumulation of oligomeric assemblies of misfolded proteins is known to induce injury gradually to diverse neuronal populations. Perhaps the foremost example of this phenomenon, both historically and in terms of its societal impact, is Alzheimer disease (AD). Progressive dysfunction of neurons in the limbic and association cortices underlies the cognitive failure of AD. This cellular dysfunction is preceded by the accumulation of extracellular aggregates of the 42-residue amyloid β-protein (Aβ) and intraneuronal aggregates of the microtubule-associated phosphoprotein tau. The purification of the respective aggregates (i.e., the amyloid plaques and the neurofibrillary tangles) from AD brain tissue and the identification of their subunit proteins were followed by the discovery of disease-causing mutations in the cognate genes. In the case of the amyloid β-protein precursor (APP), missense mutations cause a form of early-onset, autosomal dominant AD that, although rare, has a neuropathological phenotype, including the presence of abundant neurofibrillary tangles, that is indistinguishable from that of the common, late-onset disorder (reviewed in ref. 1). Thus, the linkage of familial AD to APP mutations established the first discrete cause of the disorder. In the case of the tau protein, missense or splice mutations cause not AD but the less common disorder frontotemporal dementia with parkinsonism on chromosome 17 (FTDP-17) (reviewed in ref. 2). The latter disease is marked by severe neurofibrillary tangle formation, sufficient to lead to profound dementia and the demise of the host, but no aggregates of Aβ develop. Therefore, genetics has largely resolved the contentious question of which of the two hallmark lesions, plaques or tangles, occurs first in AD. It appears that Aβ accumulation precedes and ultimately initiates the aggregation of wild-type tau protein in AD, whereas the reverse sequence of pathogenesis has not been documented.