Current Alzheimer Research - Volume 7, Issue 8, 2010

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Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/ mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ∼three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

Based on the amyloid hypothesis, studies for AD therapy have been mostly focused on removing β-amyloid. Recent results of amyloid immunotherapy raised the question whether β-amyloid is sufficient target for AD therapy. Neurofibrillary tangles (NFTs), which contain hyperphosphorylated tau, are another pathological hallmark of AD. NFTs are observed in entorhinal cortex, limbic, and neocortex over the course of clinical progression. NFTs are associated with synapse and neuron loss, suggesting that the process of NFT formation is involved in brain dysfunction. During NFT formation, tau forms a variety of different aggregation species, including tau oligomers, granules, and fibrils. Analysis of different human tau-expressing mouse lines reveals that soluble hyperphosphorylated tau, which includes tau oligomer, is involved in synapse loss, whereas granular tau formation is involved in neuronal loss. Therefore, inhibition of tau aggregation and tau phosphorylation is expected to prevent synapse loss and neuron loss, and may slow or halt the progressive dementia in AD.

Tau is a sticky protein mainly expressed by neurons, which may be found in different subcellular fractions or outside the cell. Tau is mainly associated to microtubules in the cytoplasm, although besides tubulin, tau can also bind to other proteins and to itself to form different polymers, some of which are relevant in pathological disorders. In this short review, we have revised some of the interactions involving tau, both inside or outside of the cell. Different regions of tau are involved in these interactions and some of them are more conserved throughout evolution than others.

Heat shock proteins are members of a large family that function normally in nascent protein folding and the removal of damaged proteins and are able to respond to cellular stresses such as thermal insult to prevent catastrophic protein aggregation. A number of the most common neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are characterized by such abnormal protein folding and aggregation, and the induction of the heat shock response is observed in these cases through their increased expression and often localization within the inclusions. Tau proteins form the major structural component of the neurofibrillary protein aggregates that correlate with cognitive decline in Alzheimer's disease, and appropriately this abnormal tau is targeted for corrective action by the heat shock proteins that recognize sequence motifs that are normally masked though microtubule binding. This specific heat shock response to the formation of abnormal tau can also be targeted pharmacologically to inhibit the refolding pathways and drive the degradation of tau species that are thought to be pathogenic. This review discusses the recent advances of the roles of heat shock proteins in this process.

The current review discusses microtubules and tau in the healthy brain and move on to the underling pathology of Alzheimer's disease (AD) with emphasis on tau and neurofibrillary tangles. Tangles have been associated with cognitive dysfunction causing neurodegeneration in the absence of plaques. AD, the most abundant tauopathy is characterized by β-amyloid plaques and tau tangles. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease (frontotemporal lobar degeneration), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases. Our own focused research is on activity-dependent neuroprtective protein (ADNP). Our findings show that ADNP-deficiency leads to tauopathy which is inhibited by the ADNP derived drug candidate, davunetide (originally known as NAP). The current review further describes tau as a potential diagnostic marker followed by drug candidates that are aimed at fighting tau pathology. A recent historical perspective is the final comment of the manuscript. This paper is not a comprehensive review of the literature rather it gives my own point of view in the face of many publications and a great unmet need for future therapeutics. It is hoped that davunetide, a most advanced drug in clinical development will rapidly advance as a first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD) and serve as a prototype for future therapeutic development toward modification and remedy of currently intractable neurodegenerative diseases.

Microtubule-associated protein tau has long been known for its ability to promote microtubule assembly. A less known feature of tau is its existence as a non-microtubule associated protein. Here we review the interactions of tau with other proteins, some of which interact with the microtubule binding repeat region of tau. The tau interactions with Fyn and with Pin1 have attracted the most attention and both interactions have been thought to have a role in Alzheimer's disease. The fact that tau has unknown cellular functions is further evidenced by its involvement in cell cycle activated neurodegeneration. One possible route for additional investigations stems from the presence of tau in non-neuronal cells where its characteristics have been largely unknown, although there has been a correlation between tau levels and the response of some cancer cells to microtubule-targeting chemotherapy drugs. Our studies of prostate cancer cells indicate that these cells can provide a system with phosphorylated adult tau for functional studies. In fact, structural similarities exist between Alzheimer's disease tau and prostate cancer cell tau, raising the possibility that new tau functions uncovered in prostate cancer cells will have relevance to Alzheimer's disease.

Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease. /P>

Alzheimer's disease (AD) remains a major health problem, and accounts for 50 to 60% of all cases of dementia. The two histopathological hallmarks of AD are senile plaques, composed of the β-amyloid peptide (Aβ), and intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Only a small proportion of AD is due to mutations in the genome of patients, the large majority of cases being of late onset and sporadic in origin. The relative contribution of genetics and environment to the sporadic cases is unclear, but they are accepted to be of multifactorial origin. This means that genetic and environmental factors can interact together to induce or accelerate the disease. Among environmental factors, studies suggest that hypothermia may contribute to the development and exacerbation AD. Here, we review the preclinical data involving hypothermia with tau and Aβ, as well as clinical evidence implicating hypothermia in the development of AD.

Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinson's disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotypespecific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.