Introduction br Alzheimer pathology A and
Alzheimer pathology: Aβ and Tau Amyloid β protein (Aβ) plays an important role in AD pathogenesis. At the molecular level, senile amyloid plaques and neurofibrillary tangles (NFT) are two neuropathological hallmarks of AD . Mutations in genes encoding amyloid precursor protein (APP) or presenilin (PS) cause early onset familial AD (FAD), and one or two copies of the apolipoprotein E (apoE) ε4 allele is a major risk factor for late-onset sporadic AD. Aβ is generated by sequential cleavages of the APP by β- and γ-secretases. First, APP is proteolytically processed by β-secretase (BACE1) and generates a 12 kDa C-terminal stub of APP (C99); second, C99 is cleaved by γ-secretase to yield two major species of Aβ ending at residue 40 (Aβ40) or 42 (Aβ42) [2,3]. Genetic studies show that detrimental familial AD-linked missense mutations in APP or PS increase the ratio of 42 residue of Aβ (Aβ42) to a more common 40-residue of Aβ (Aβ40) and cause early onset AD, while a beneficial mutation in APP leads to decreased Aβ production and those carriers maintain intact cognitive function at advanced ages . ApoE has three major isoforms, ApoEε2, ε3 and ε4. ApoEε4 allele is the strongest known risk factor for AD. Brains of sporadic AD patients carrying ApoEε4 allele were found to have increased density of Aβ deposits, limited capability to clear Aβ, and enhanced neuroinflammation . The Aβ42 peptide has been the center of investigation and the target for therapeutic exploration. In AD, the protein subunit of the amyloid plaques, Aβ, does not occur as a single molecular species; many different Aβ-containing peptides have been detected in human cerebrospinal fluid (CSF) and/or brain [6,7]. The most common Aβ isoform in vivo is Aβ40, i.e., a peptide that begins at Asp1 and terminates at Val40 of the Aβ region of APP. Increased accumulation of Aβ42, a peptide that differs from Aβ40 by the inclusion of Ile41 and Ala42, is particularly associated with development of AD. The extra two hydrophobic wh4 receptor of Aβ42 greatly enhance its aggregation propensity , leading to accelerated formation of small (low-n) Aβ oligomers (oAβ), larger intermediate assemblies like protofibrils, and eventually the typical ∼8 nm amyloid fibrils found abundantly in neuritic plaques and amyloid-bearing micro vessels. Small, soluble oligomers of Aβ have been linked to neuronal toxicity and synaptic failure (for review, see ). The ratio of Aβ42/Aβ40, rather than the total amount of Aβ, has been shown to correlate with the age of onset of FAD  and with the amount of plaques in mouse models [11,12]. Aβ42 constitutes approximately 10% of total Aβ species  and is more prone to aggregation than Aβ 40 [8,14], Furthermore, Aβ40 may play an antagonistic role in preventing Aβ42 aggregation in vivo [11,12] and in vitro [, , ]. Expression of Aβ42, rather than Aβ40, in Drosophila and mice led to the formation of Aβ plaques [18,19]. Therefore, specific inhibition of γ-secretase activity for Aβ42 generation would be an appealing strategy for the treatment of AD [20,21]. The Aβ peptide is closely linked to a second AD pathological protein, tau. This intracellular hallmark of AD is the paired helical filament (PHF) in NFT containing hyperphosphorylated tau. Mutation in the tau gene causes frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) . Transgenic mice expressing mutant tau show close association of mutation to NFT formation and neurodegeneration [23,24]. Furthermore, Aβ has been shown to drive tau pathology in vivo . The normal microtubule-associated tau gradually loses association with microtubules and hyperphosphorylated tau forms PHF which accumulate in neuronal cytoplasm as the major component of the NFT. Glycogen synthase kinase-3β (GSK3β) is one of several microtubule-associated kinases responsible for tau phosphorylation . GSK3β has been found to phosphorylate a number of sites on tau that were identified by nanoelectrospray mass spectrometry, including the residue Thr181 to form pTau181 .