Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes

Abstract

BackgroundDendritic simplification, a key feature of the neurodegenerative triad of Alzheimer’s disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.ResultsTo investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions.ConclusionsThe data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity.

Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers

“…As consequence, a correct cell morphology of neurons and astrocytes is restored. We thus provide a new mechanism of microtubule destabilization driven upstream by human AβOs, through the post-translational modulation of tau and tubulin, extending previous findings in AD neuronal models [39,40].…”

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

“…Amyloid plaques are primarily comprised of Aβ which is derived from sequential cleavages of APP by β- and γ-secretases (Zhang et al, 2011; Audrain et al, 2016). Cumulative evidence demonstrates that Aβ and tau are neurotoxic and can trigger a cascade of neurodegenerative processes ending in neuronal death, suggesting that overproduction/accumulation of Aβ and tau in vulnerable brain regions is the primary influence driving AD pathogenesis (Hardy and Selkoe, 2002; Gautam et al, 2015; Golovyashkina et al, 2015; Popugaeva et al, 2015). …”

Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro

“…To assess the effect of microtubule stabilisation on neuronal viability and the capacity for neurite extension, we performed an AlamarBlue ® cell viability assay, nuclear morphology analysis and evaluation of neurite extension of immature embryonic YFP positive mouse cortical neurons. EpoD was administered to developing cultures by bath application in concentrations of 0.1 nM, 1 nM, 10 nM and 100 nM, which was replaced at 24 hour time intervals for 4 days 28,38,39 .…”