Abstract
Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2–4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr216 being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3β-Tyr216 was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD.
Highlights
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder of the CNS that is characterized by progressive neurological deficits, including involuntary movements, psychiatric disturbances and cognitive decline.[1]
Using RPLP0 as a reference gene (Figure 2a), we found that Glycogen synthase kinase-3β (GSK-3β) mRNA transcripts were significantly increased in the whole HD group (F = 14.25; P = 0.00063), as well as in the separate HD Grades 2–4 relative to the CT cases, with the Grade 4 group reaching the highest level of significance (F = 24.385; Po0.001) as compared with Grade 2 (F = 5.775; P = 0.036) and Grade 3 (F = 6.036; P = 0.027) (Figure 2a)
Extensive immunohistochemistry analyses corroborated our findings by showing increased protein levels for GSK-3β and active pGSK-3β-Tyr[216] in both HD hippocampal neurons and astrocytes as a function of disease severity
Summary
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder of the CNS that is characterized by progressive neurological deficits, including involuntary movements (e.g., chorea, dystonia and gait abnormalities), psychiatric disturbances and cognitive decline.[1] Notably, cognitive impairments appear early in the disease course and profoundly impact on the patients’ quality of life.[2,3] This clinical profile reflects the fact that while the major pathology of HD involves the striatum and deep layers of the cerebral cortex,[1,4,5,6,7] it is not restricted to this site but involves many other areas of the CNS from disease onset, including the hippocampus.[8,9,10] Both neuronal loss in the hippocampal CA1 region and volumetric reduction on MRI have been reported in patients,[8,9,10] which are seen in animal models of the disease All of this suggests that there is a selective vulnerability of hippocampal neurons to the disease process that may explain some of the cognitive and psychiatric deficits commonly seen in HD.[11]. GSK-3β disruption of glia–neuron crosstalk in HD F L’Episcopo et al for neuronal survival, and this cell may indirectly contribute to increase neuronal vulnerability and/or neuronal cell death.[13,14,15,16,17,18]
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