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Whether accumulation of Aβ peptide, hyperphosphorylation of tau, or cell death is generated first in Alzheimer disease, and whether any of these are related, is still a matter of debate. Transgenic mice demonstrating an increased burden of Aβ deposits do not always exhibit hyperphosphorylated tau, and mice overexpressing mutant tau do not exhibit Aβ aggregates. Nevertheless, numerous studies have provided convincing evidence that Aβ and tau are causally related. Indeed, injection of Aβ(1-42) fibrils into P301L tau transgenic mice  or rabbit brains  accelerates the formation of phosphorylated tau, and transgenic mice overexpressing both mutant amyloid precursor protein and mutant tau exhibit marked neurofibrillary degeneration . Such results are in accordance with in vitro results showing that synthetic Aβ, when added to cultured neurons, leads to increased tau phosphorylation [4-6]. Collectively, these latter results suggest that Aβ accumulation precedes and triggers phosphorylated tau deposition. In accordance are data from the LaFerla group, demonstrating that Aβ accumulation precedes tangle deposition in a triple transgenic model of AD [7,8].
Additional studies further demonstrate the solid functional link between Aβ and phosphorylated tau. Aβ-induced caspase activation triggers cleavage of tau and generates enhanced polymerized products . Liu and colleagues have also shown that blocking tau expression and phosphorylation with an antisense oligonucleotide completely inhibits Aβ toxicity in differentiated neurons from rat cultures . On the other hand, Rapoport and colleagues have shown that cultured hippocampal neurons expressing either mouse or human tau proteins degenerate in the presence of Aβ fibrils, while tau-depleted neurons show no signs of degeneration . These latter results provide strong evidence that tau expression is required for Aβ-induced neurotoxicity in primary cultures of neurons.
Taken together, although all the above data indicate that Aβ and tau are related and that Aβ accumulation is an upstream event to tau hyperphosphorylation, the mechanistic links underlying Aβ-induced tau phosphorylation are still to be determined.
Now, in this noteworthy article, Michelle King, George Bloom, and colleagues show strong and convincing data that in cells transfected with tau, as well as in primary rat cortical neurons, prefibrillar, but not fibrillar, Aβ42 causes tau to dissociate from microtubules, which then completely and rapidly disassembled. In these experiments, tau appears to make microtubules acutely sensitive to prefibrillar Aβ42. Interestingly, Aβ-induced microtubule disassembly did not correlate with increased tau phosphorylation. These results by King and Bloom may reinforce the hypothesis that Aβ aggregates and phosphorylated tau deposits are less neurotoxic, if not neuroprotective, than prefibrillar Aβ and tau. Confirmation of microtubule disassembly in transgenic mice at a stage before plaque formation takes place will add important insights into intracellular mechanisms that lead to neuronal impairment in Alzheimer disease.
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King and colleagues expanded on a previous report by Rapport and colleagues that showed that tau is essential for β amyloid-induced neurotoxicity. In this report, King et al. show that a prefibrillar form of Aβ induced tau-dependent microtubule disassembly. When Aβ neurotoxicity was first reported by Bruce Yankner, researchers in the field discussed whether Aβ could be neurotoxic, because the presence of soluble Aβ showed no neurotoxicity. When it was shown that aged and Congo red-positive fibrillar Aβ showed neurotoxicity, this dispute was settled. Recently, oligomeric Aβ is believed to be a toxic form of Aβ. However, King and colleagues now claim that freshly solubilized Aβ42 and Aβ40 induce the same effect as tau-dependent microtubule disassembly without affecting tau phosphorylation. Although they confirmed that Aβ42 formed an A11 immunoreactive Aβ oligomer, they say that Aβ42 mostly exists as monomers. We still do not know which form of Aβ affects microtubule stability.
Their report raises questions about the role of Aβ in AD development. Aβ forms various aggregate structures. Do these different aggregates activate different mechanisms that lead to neurotoxicity? For example, could some aggregates directly induce apoptosis, while other aggregates affect microtubule stability? If diffusible Aβ aggregates induce tau-dependent microtubule disassembly that leads to neuronal dysfunction, why would symptoms of AD start with impairment of entorhinal/hippocampal function where there is no Aβ deposition? Based on the β amyloid hypothesis, Aβ directly affects neurons and induces neuronal dysfunction with NFT formation and neuronal loss. Tau-dependent microtubule disassembly may contribute to neuronal dysfunction before neuronal death and the formation of NFTs through synapse loss as Paul Coleman mentioned. However, Aβ deposition does not start in the entorhinal/hippocampal region in the AD brain (although APP Tg mice start from the hippocampal region and memory impairment). Even if it is not fibrillar Aβ but diffusible Aβ aggregates that lead to neuronal dysfunction, it is difficult to explain the emergence of AD symptoms by pointing to a specific neuronal dysfunction. We may need a more practical explanation for the development of AD.