Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Abstract

To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-␤ protein (A␤). This complex enhances tau phosphorylation by GSK3␤, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A␤ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A␤ peptides in the mid to C-terminal regions of A␤. This binding is also significantly decreased by GSK3␤ phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A␤ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A␤ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and A␤ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A␤ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A␤ nucleation. Blocking the sites where A␤ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.immunochemistry ͉ neurofibrillary tangles ͉ senile plaques ͉ surface plasmon resonance S o far, no reasonable interpretation has been advanced to explain the simultaneous appearance of senile plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Senile plaques develop extracellularly with the main component being aggregated amyloid-␤ protein (A␤), whereas NFTs develop intracellularly with the main component being aggregated forms of phosphorylated tau. The two aggregation processes appear to occur independently, because NFTs develop in neuronal cell bodies and senile plaques develop around their nerve endings. This observation has led to two schools of thought regarding AD causation. The tau hypothesis holds that the disease is driven by tangles resulting from an excess of tau phosphorylation or a deficiency of its dephosphorylation (1). The hypothesis does not explain plaques. The amyloid hypothesis holds that the disease is driven by excess production of A␤ (2, 3). This hypothesis does not explain NFTs. Nevertheless, the amyloid cascade hypothesis is dominant because mutations in amyloid precursor protein (APP), which enhance A␤ production, cause autosomal dominant AD but not other types of dementia (2). On the other hand, mutations in tau that promote tau aggregation produce autosomal dominant frontotemporal dementia but not AD (4, 5). As a result, the presumption is that excess A␤ is a major cause and an upstream event of AD tangle formation, but exactly how an A␤ excess ...

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

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Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

“…Moreover, APP transport was shown to be impaired by elevated tau, suggesting a possible link of the 2 proteins (28,29). Oligomeric A␤ can attach to tau (30,31), causing a rapid dissociation of tau from microtubules and a collapse of axonal structures leading initially to synaptic malfunction and ultimately, neuronal death. Interestingly, A␤ may not only be located to the cell surface but also directly interact with mitochondria (20) as it can be imported into mitochondria via the translocase of the outer membrane (TOM) machinery (32).…”

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

“…How Aβ mediates alteration and aggregation of Tau is uncertain, although three major mechanisms have been proposed: (i) Aβ activates kinases that phosphorylate Tau (Hernández & Avila, 2010; Llorens‐Martín et al ., 2014) altering its capacity to bind tubulin; (ii) Aβ alters the proteasomal degradation of Tau, increasing its concentration in free state (Oddo et al ., 2009); (iii) Aβ intracellular aggregates have a nucleation effect on Tau (Guo et al ., 2006; Bolmont et al ., 2007). The third hypothesis is supported by the occurrence of Tau pathology in different types of cerebral amyloidosis (Holton et al ., 2001; Giaccone et al ., 2008).…”