Several publications are referenced in this application by author name, year and journal of publication in parentheses in order to more fully describe the state of the art to which this invention pertains. Several patents are also referenced throughout the specification. The disclosure of each of these publications and patent documents is incorporated by reference herein.
Approximately 4 million Americans have Alzheimer's Disease, and almost 45,000 Americans per year die of the disease (Hoyert, et al., 2001, Final Data for 1999, National Vital Statistics Report, 49: 6). One in ten persons over the age of 65, and nearly half of those over 85 have Alzheimer's (Alzheimer's Association, 2002). Alzheimer's disease is the most common form of dementia in today's elderly population (Mandelkow, E., 1999, Nature, 402: 588-589). The symptoms of Alzheimer's generally begin with a subtle decline in memory, and progress to include changes in personality, impaired learning ability, a decline in language function, the deterioration of visuospatial skills, and motor dysfunction. Eventually, the disease may cause extrapyramidal side effects (EPS), myoclonus, psychosis, seizures, aphasia, and primitive reflexes. This progression of symptoms is a result of increasing brain damage (Lau et al., 2002).
Beta-amyloid deposition is an established diagnostic marker of Alzheimer's disease, and is believed to be the primary cause of the disease. Neurofibrillary tangles (NFTs), which are comprised primarily of hyperphosphorylated tau protein and ubiquinated proteins are correlated with Alzheimer's disease progression, symptoms, and disabilities. Thus hyperphosphorylated tau protein is a distinguishing feature in degenerative disease progression of Alzheimer's and other neurodegenerative disorders.
Tau proteins are microtubule associated proteins that are abundant in the central nervous system, and are predominantly expressed in axons. Human tau proteins are encoded by a single gene consisting of 16 exons on chromosome 17q21, and six central nervous system isoforms are generated by alterative mRNA splicing.
The primary function of tau is to bind to, and stabilize microtubules, thereby promoting microtubule polymerization. The microtubule binding domains of tau are localized to the c-terminal portions of tau. Tau also contains numerous phosphorylation domains, many of which flank the microtubule binding domains. Phosphorylation is believed to play a significant role in microtubule binding by tau (Lee, et al., 2001, Annual Review of Neuroscience, 201: 1121-1159).
Aberrant phosphorylation of tau is observed in many neurodegenerative disorders. In addition to Alzheimer's disease, tau-positive neurofibrillary pathology has been linked to Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Argyrophilic grain dimentia, Corticobasal degeneration, Creutzfeldt-Jakob disease, Dementia pugilistic, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Frontotemporal dementia with parkinsonism linked to chromosome 17a, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Myotonic dystrophy, Niemann-Pick disease, Non-Guamanian motor neuron disease with nerofibrillary tangles, Pick's disease, Postencephilitic parkinsonism, Prion protein cerebral amyloid angiopathy, Progressive subcortical gliosis, Progressive supranuclear palsy, Subacute sclerosing panencephalitis, and tangle only dementia. Neurodegenerative disorders which are tau related are known in the art as “tauopathies.” (Lee, et al., supra).
Hyperphosphorylation of tau causes tau to dissociate from microtubules, and form tau protein aggregates which are the primary component of NFTs. Thus, identifying those protein kinases and protein phosphatases which regulate tau phosphorylation holds major promise for finding new treatments and therapeutic targets for ameliorating the symptoms of Alzheimer's and other neurodegenerative disorders.
Protein kinases implicated in tau regulation include mitogen-activated protein kinase (MAPK), glycogen synthase kinase 3β (GSK-3β), cyclin-dependent kinase 2 (cdk2), cdk5, Ca2+/calmodulin-dependent protein kinase II, and MT affinity regulating kinase (Lee et al., supra). A great deal of research has focused on GSK-3β and cdk5. GSK-3β is ubiquitously expressed, and is known to be involved in cytoskeletal protein phosphorylation, cell cycle regulation, and cell death. Cdk5 is composed of p35 and p25 heterodimer, and is also ubiquitously expressed. The p25 component of cdk5 is unregulated in the brains of Alzheimer's Disease patients. Both GSK-3β and cdk5 are known to phosphorylate tau in vitro, but the link between these kinases, the formation of NFTs, and the progression of Alzheimer's and other tau related neurodegenerative disorders is still unclear (Lau, et al., 2002, Current Topics in Medicinal Chemistry, 2: 395-415.)
As those skilled in the treatment of Alzheimer's disease and tauopathies appreciate, a need exists for improved therapeutic agents for the treatment of these disorders. Identification of a human brain specific kinase which has a clear link to Alzheimer's disease and other tauopathies, provides an ideal target for the development of diagnostics and therapeutics for these pathologies.
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