Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D

Abstract

Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer’s disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, and spine morphology progressively changes from mushroom-shaped to stubby. We demonstrate that spine changes are completely reversed within few days after blocking amyloid-β (Aβ) production with the gamma-secretase inhibitor DAPT. We show that the microtubule disrupting drug nocodazole leads to spine loss similar to Aβ expressing cultures and suppresses DAPT-mediated spine recovery in slices from APP transgenic mice. Finally, we report that epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in model neurons, completely reverses Aβ-induced spine loss and increases thin spine density. Taken together the data indicate that Aβ causes spine changes by microtubule destabilization and that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reduce spine loss during the preclinical stage of AD.

Dysregulation of neuronal calcium homeostasis in Alzheimer's disease – A therapeutic opportunity?

“…We and others previously proposed that mushroom spines are strongly eliminated in AD and that loss of mushroom spines may underlie cognitive decline during the progression of the disease [20–22]. Consistent with this hypothesis, reduction in hippocampal mushroom spines was observed in different experimental mice models of AD, including PS1-M146V-KI mice [23], newly generated APP-KI mice [24, 25], in conditions of amyloid synaptotoxicity in vivo and in vitro [26], and ex vivo in hippocampal slice cultures from APP SDL transgenic mice [27, 28]. We suggest that mushroom spines loss is an early event, which precedes more severe neurodegenerative changes.…”

Geniposide Alleviates Amyloid-Induced Synaptic Injury by Protecting Axonal Mitochondrial Trafficking

“…Dendritic spine density and morphology significantly changed in transgenic AD mouse models (Perez-Cruz et al, 2011; Penazzi et al, 2016); therefore, the spine phenotypes in cultured primary hippocampal neurons were investigated using CellTracker CM-DiI, and dendritic spines were categorized into three groups (mushroom, stubby, and thin).…”

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

“…In addition, MT dynamicity appears to increase with age and in pathological conditions (Penazzi et al. , 2016a, b). The change in MT spacing will affect the apparent association and dissociation rates of tau and could affect the influence of mutations or phosphorylation on the interaction with the axonal MT array, thereby contributing to mislocalization of tau under pathological conditions.…”