Linking amyloid-β and tau: amyloid-β induced synaptic dysfunction via local wreckage of the neuronal cytoskeleton.

In Alzheimer's disease (AD), amyloid-β (Aβ) is the major component of extracellular plaques, whereas the microtubule-associated protein tau forms the main component of intracellular tangles. In contrast to frontotemporal dementias and other neurodegenerative diseases, both proteins form pathological aggregates and are considered key players for the development of AD. However, the connection between Aβ and tau and the functional loss of neurons and synapses, which ultimately lead to cognitive impairments, is still not well understood. Making use of primary neurons exposed to Aβ oligomers, we sought to determine how tau mediates the Aβ-induced neuronal dysfunction. Additionally, we asked how the microtubule cytoskeleton is involved in the combined Aβ and tau toxicity. We exposed mature primary rat neurons with developed synapses to Aβ oligomers and used immunofluorescence and electron microscopy to investigate tau, actin, neurofilament and microtuble cytoskeleton changes. Aβ oligomers preferentially associate with synapses, notably dendritic spines, throughout the neuronal cell culture. As a consequence, endogenous tau gets missorted from the axonal into the somatodendritic compartment in a subset of cells. These missorted cells also display missorting of neurofilaments, and a dramatic loss of microtubules, which can be prevented by the microtubule stabilizer taxol. Aβ causes tau missorting, loss of neuronal cell polarity and loss of dendritic microtubules. This in turn leads to impaired organelle/mitochondria transport, whereby synapses cannot be maintained properly and eventually decay. The data support the view that the microtubule cytoskeleton is a valid therapeutic target in AD. Copyright © 2011 S. Karger AG, Basel.