Aβ Inhibition of Kinesin 5 Disrupts the Localization and Function of Membrane Proteins: Implications for Neuronal Responses to Neurotrophins, Neurotransmitters, Glucose, and Lipids in Ad (original) (raw)
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Tau Neurofibrillary Pathology and Microtubule Stability
Journal of Molecular Neuroscience, 2002
We previously reported that nonomolar concentrations of Taxol and several structurally diverse microtubule (MT)-stabilizing agents significantly enhanced the survival of neurons in the presence of fibrils of amyloid β peptide (Aβ). Pretreatment of neurons with MT-stabilizing drugs also blocked Aβ-induced activation of tau hyperphosphorylation. Although tau is a substrate for several kinases, we initially focused on cdk5, as this tau kinase has been shown to be activated in Aβ-treated neurons and Alzheimer's disease (AD) brain. In an in vitro kinase assay, Taxol inhibited activation of cdk5 by Aβ. In addition, the proposed cellular cascade in which calpain activation leads to cleavage of the cdk5 regulator, p35, to the strong kinase activator p25 was also prevented. Taxol did not directly inhibit the activity of either cdk5 or calpain, indicating that other cellular components are required for the effect of the drug on Aβ activation of tau phosphorylation. Our results suggest that drugs that interact with MTs can alter signaling events in neurons, possibly because some MTs play a role in organizing protein complexes involved in responses to Aβ. Thus the cytoskeletal network may serve as a biosensor of cellular well-being.
Journal of Neuroscience Research, 2009
The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin-and dyneindependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited antero-grade (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
The A 1-42 peptide regulates microtubule stability independently of tau
Journal of Cell Science, 2014
Interference with microtubule stability by beta-amyloid peptide (Aβ) has been shown to disrupt dendritic function and axonal trafficking, both early events in Alzheimer's disease. However, it is unclear whether Aβ regulation of microtubule dynamics can occur independently of its action on tau. RhoA has been implicated in neurotoxicity by Aβ but the mechanism by which this activation generates cytoskeletal changes is also unclear. We found that oligomeric Aβ1-42 induced the formation of stable detyrosinated microtubules in NIH3T3 cells and this function resulted from the activation of a RhoA-dependent microtubule stabilization pathway regulated by integrin signaling and the formin mDia1. Induction of microtubule stability by Aβ was also initiated by APP-dimerization and required caspase activity, two previously characterized regulators of neurotoxicity downstream of Aβ. Finally, we found that this function was conserved in primary neurons and abolished by Rho inactivation, reinfo...
Journal of Cell Biology, 1998
The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins. Mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. These effects are caused by tau's binding to microtubules and slowing down intracellular transport by preferential impairment of plus-end-directed transport mediated by kinesin-like motor proteins. Since in Alzheimer's disease tau protein is elevated and mislocalized, these observations point to a possible cause for the gradual degeneration of neurons.
Amyloid-β peptide binds to microtubule-associated protein 1B (MAP1B
Neurochemistry International, 2008
Extracellular and intraneuronal formation of amyloid-beta aggregates have been demonstrated to be involved in the pathogenesis of Alzheimer's disease. However, the precise mechanism of amyloidbeta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloidbeta to a number of targets have deleterious effects on cellular functions. In the present study we have shown for the first time that amyloid-beta 1-42 bound to a peptide comprising the microtubule binding domain of the heavy chain of microtubule-associated protein 1B by the screening of a human brain cDNA library expressed on M13 phage. This interaction may explain, in part, the loss of neuronal cytoskeletal integrity, impairment of microtubule-dependent transport and synaptic dysfunction observed previously in Alzheimer's disease.
PLoS ONE, 2013
Pathologic aggregation of b-amyloid (Ab) peptide and the axonal microtubule-associated protein tau protein are hallmarks of Alzheimer's disease (AD). Evidence supports that Ab peptide accumulation precedes microtubule-related pathology, although the link between Ab and tau remains unclear. We previously provided evidence for early co-localization of Ab42 peptides and hyperphosphorylated tau within postsynaptic terminals of CA1 dendrites in the hippocampus of AD transgenic mice. Here, we explore the relation between Ab peptide accumulation and the dendritic, microtubule-associated protein 2 (MAP2) in the well-characterized amyloid precursor protein Swedish mutant transgenic mouse (Tg2576). We provide evidence that localized intraneuronal accumulation of Ab42 peptides is spatially associated with reductions of MAP2 in dendrites and postsynaptic compartments of Tg2576 mice at early ages. Our data support that reduction in MAP2 begins at sites of Ab42 monomer and low molecular weight oligomer (M/LMW) peptide accumulation. Cumulative evidence suggests that accumulation of M/LMW Ab42 peptides occurs early, before high molecular weight oligomerization and plaque formation. Since synaptic alteration is the best pathologic correlate of cognitive dysfunction in AD, the spatial association of M/LMW Ab peptide accumulation with pathology of MAP2 within neuronal processes and synaptic compartments early in the disease process reinforces the importance of intraneuronal Ab accumulation in AD pathogenesis. Citation: Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2013) Accumulation of Intraneuronal b-Amyloid 42 Peptides Is Associated with Early Changes in Microtubule-Associated Protein 2 in Neurites and Synapses. PLoS ONE 8(1): e51965.
Microtubule dynamics and the neurodegenerative triad of Alzheimer's disease: The hidden connection
Journal of Neurochemistry, 2017
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is, on a histopathological level, characterized by the presence of extracellular amyloid plaques composed of the protein fragment Aβ, and intracellular neurofibrillary tangles, which contain the microtubule‐associated protein tau in a hyperphosphorylated state. In AD defects in microtubule (MT) assembly and organization have also been reported; however, it is unclear whether MT abnormalities have a causal and early role in the disease process or represent a common end point downstream of the neurodegenerative cascade. Recent evidence indicates that microtubule‐stabilizing drugs prevent axonopathy in animal models of tauopathies and reverse Aβ‐induced loss of synaptic connectivity in an ex vivo model of amyloidosis. This could suggest that MT dysfunction connects some of the degenerative events and provides a useful target to simultaneously prevent several neurodegenerative processes in AD. Here, we descri...