Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

Abstract

The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…Oral administration of the aminothiazole AR-A014418 resulted in decreased tau aggregation in a transgenic mouse model of P301L tau. 131,132 Lithium, a well-characterized mood-stabilizer, competes with magnesium for GSK-3 binding; it leads to reduced tau-phosphorylation, aggregation and axonal degeneration in transgenic mice. 133,134 Valproate, another mood-stabilizing drug (and an antiepileptic), also inhibits GSK-3␤ and is currently being tested in clinical AD trials.…”

New directions for frontotemporal dementia drug discovery

“…There is considerable evidence showing that GSK3 phosphorylates tau and hence could be target for inhibition to prevent pathological tau phosphorylation in AD and FTD tauopathies [2,4,7,14]. GSK3beta may also cooperate with other, non-tau proteins, to contribute to neuronal disruption.…”

“…Thus, this kinase may have effects on neuritic dystrophy that are independent of tau. Potent small molecule inhibitors of GSKbeta have been developed and some appear to be highly specific for GSK3 while not appreciably affecting other kinases [2,4,7,14,16,17]. These molecules inhibit tau phosphorylation in vitro and in vivo and they prevent tau aggregates in transgenic (Tg) mice expressing aggregate prone tau mutants.…”

“…CDK5 phosphorylates tau at several sites that have been linked to disease and it may be an ideal target for drug discovery because it is kept in its active form not by phosphorylation, but by the binding of a protein partner called p25 [1,4,16,17]. Screens for small molecules that inhibit this kinase in an ATP site-independent manner have turned up three classes of molecules.…”

“…Most insights into tauopathies have come from studies of AD, but prominent tau abnormalities are recognized as the defining neuropathology in close to half of clinically diagnosed FTDs cases, and these are referred to as tauopathies due to accumulations of insoluble hyperphosphorylated tau proteins in neurons and/or glial cells [4,8,12,16,17]. For example, besides atrophy of the frontal and temporal lobes with superficial spongiosis, Pick's disease (PiD) is characterized by large numbers of tau-positive spherical cytoplasmic inclusions called Pick bodies that are encountered in particular in the hippocampus.…”