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Modifying Rap1-signalling by targeting Pde6? is neuroprotective in models of Alzheimer's disease.

ABSTRACT: BACKGROUND:Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. METHODS:Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6? normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. RESULTS:The newly identified inhibitors of the Rap1-Pde6? interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6? accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. CONCLUSION:Targeting the Pde6?-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease.

SUBMITTER: Dumbacher M

PROVIDER: S-EPMC6158915 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease.

Dumbacher Michael M Van Dooren Tom T Princen Katrien K De Witte Koen K Farinelli Mélissa M Lievens Sam S Tavernier Jan J Dehaen Wim W Wera Stefaan S Winderickx Joris J Allasia Sara S Kilonda Amuri A Spieser Stéphane S Marchand Arnaud A Chaltin Patrick P Hoogenraad Casper C CC Griffioen Gerard G

Molecular neurodegeneration 20180926 1

<h4>Background</h4>Neuronal Ca<sup>2+</sup> dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca<sup>2+</sup> influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca<sup>2+</sup> signalling and neuronal hyperactivity, without overly ...[more]

PMID: 30257685

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Project description:Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression.This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc).Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN3) (15 mg/kgBw/day) and aluminium chloride (AlCl3) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN3; E received AlCl3; F received NaN3 then GBc subsequently; G received AlCl3 then GBc subsequently; H received NaN3 and GBc simultaneously while I received AlCl3 and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays.Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl3 and NaN3. These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis.Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl3 and NaN3-induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.

Dataset Information

Modifying Rap1-signalling by targeting Pde6? is neuroprotective in models of Alzheimer's disease.

Publications

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease.

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