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Azheimer's disease: senile plaques & neurofibrillary tangles
Alzheimer's disease (AD) is characterized by the presence in the brain of two aberrant structures, senile plaques (SP) and neurofibrillary tangles (NFTs) [1]. The major component of SP is the β-amyloid peptide (Aβ), a fragment of the amyloid precursor protein (APP) [2,3]. This fragment is produced after the cleavage of APP by two proteases, β- and gγ-secretases [4]. The main component of a NFT is the microtubule-associated protein tau, which is aberrantly hyperphosphorylated [5], and glycogen synthase kinase (GSK)-3 is the protein kinase able to modify sites on the tau molecule [6].
AD has been classified into two types: one with familiar origin (very few cases) and the other of sporadic origin (a high proportion of the cases). Familiar AD (FAD) is associated with mutations in three genes APP , PS-1 and PS-2 which are responsible for the expression of the proteins APP, PS-1 and PS-2; PS-1 and PS-2 are components of a protein complex that displays gγ-secretase activity [4]. Based on these observations, a Aβcascade hypothesis was proposed to explain AD [7]. This hypothesis suggests that mutations in APP , PS-1 or PS-2 facilitate the accumulation of Aβand the presence of SP, which results in the occurence of other events, such as tau phosphorylation. However, the validity of the Aβcascade hypothesis as an explaination for AD has been partially questioned. One of these concerns comes from the assumption that PS mutations that yield an increased amount of Aβpeptide should induce a faster onset of FAD. However, this is not the case [8] as the amount of Aβgenerated in cells transfected with different PS-1 mutations did not correlate with the starting age of FAD caused by that mutation. In addition, a novel PS-1 mutation has recently been described in a patient with Pick-type tauopathy in the absence of extracellular Aβdeposits [9]. In support of this, the severity of dementia has been correlated with the accumulation of NFTs in different brain regions [10], while in the case of the other hallmark of AD, SP, a correlation has not been demonstrated [11-13]. At present, the toxicity of these aberrant structures in their intracellular [14,15] or extracellular form [16] is under discussion, although the emerging idea is that the toxic...