Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: the interaction of Aβ and sphingolipid mediators as a therapeutic target

Jazvinšćak Jembrek, Maja; Babić, Mirjana; Pivac, Nela; Hof, Patrick R.; Šimić, Goran (2013) Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: the interaction of Aβ and sphingolipid mediators as a therapeutic target. Translational Neuroscience, 4 (4). pp. 466-476. ISSN 2081-3856

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Official URL: http://www.degruyter.com/view/j/tnsci.2013.4.issue...

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen- synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β- secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ- hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.

Item Type:

Article

Uncontrolled Keywords:

Alzheimer’s disease; Tau hyperphosphorylation; Glycogen-synthase kinase 3β; Amyloid β; Sphingolipids

Subjects:

BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
BIOMEDICINE AND HEALTHCARE > Clinical Medical Sciences
SOCIAL SCIENCES > Psychology

Divisions:

Division of Molecular Medicine

Projects:

Project title	Project leader	Project code	Project type
Farmakogenomika i proteomika serotoninskog i kateholaminskog sustava	Dorotea Muck-Šeler	098-0982522-2457	MZOS
Molekularna podloga i liječenje psihijatrijskih i stresom izazvanih poremećaja	Nela Pivac	098-0982522-2455	MZOS
Stres, GABA-A receptori i mehanizmi djelovanja neuropsihofarmaka	Dubravka Švob Štrac	098-0000000-2448	MZOS
Fosforilacija tau proteina u razvitku i Alzheimerovoj bolesti	Goran Šimić	108-1081870-1942	MZOS
Otkrivanje i praćenje bioloških biljega radi rane terapijske intervencije u Alzheimerovoj bolesti	Goran Šimić	IS-09/16	HRZZ