Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease

Abstract

β-Amyloid (Aβ) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aβ, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3β, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3β after exposure to oligomeric Aβ in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3β, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3β prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3β inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3β inhibition robustly decreased the oligomeric Aβ load in the mouse brain. All these findings support the idea that GSK3β is aberrantly activated by the presence of Aβ, and contributes, at least in part, to the neuronal anatomical derangement associated with Aβ plaques in AD brains and to Aβ pathology itself.

Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology

“…Axonal morphology was better preserved in high probability mismatches than in demented Alzheimer's disease cases Studies in humans and transgenic mice have demonstrated a widespread alteration in the geometry and morphology of dendrites and axons, including disrupted trajectories and dystrophic swellings, which occurs both near plaques, especially fibrillar thioflavin-S reactive plaques, but also distant from them in Alzheimer's disease (Knowles et al, 1999;Le et al, 2001;D'Amore et al, 2003;Spires et al, 2005;Coma et al, 2010;DaRocha-Souto et al, 2012). These changes likely contribute to altered neural system function and cognitive impairment in Alzheimer's disease.…”

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

“…Overactivation of GSK-3b in neurons is associated with cognitive impairments, Ab production, neuronal death, and neuroinflammation (Bhat et al, 2004;Hooper et al, 2008). GSK-3b overactivation results in Tau hyperphosphorylation, microtubule disruption, and neuronal apoptosis (Kosik, 1992;Bhat et al, 2000, Hetman et al, 2000Lucas et al, 2001;Beurel and Jope, 2006;DaRocha-Souto et al, 2012). Inhibition of GSK-3b activity also directly participates in synaptic plasticity and memory consolidation by allowing, for instance, a blockade of long-term depression following the induction of long-term potentiation (Peineau et al, 2007).…”

Ibuprofen and Lipoic Acid Conjugate Neuroprotective Activity Is Mediated by Ngb/Akt Intracellular Signaling Pathway in Alzheimer's Disease Rat Model

“…Multiple studies in different models have extensively stated a critical role for the cAMP signaling pathway and CREB-mediated gene expression in cell survival and also in different forms of synaptic plasticity related to learning [18], and it is well known that inhibition of the CREB-mediated transcriptional program is involved in Aβ-induced neuronal derangement and AD progression [19,20]. …”