Regulation of tau isoform expression and dementia

Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, 1660 S. Columbian Way, Seattle, WA 98108, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2005; 1739(2-3):104-15. DOI: 10.1016/j.bbadis.2004.08.009
Source: PubMed

ABSTRACT In the central nervous system (CNS), aberrant changes in tau mRNA splicing and consequently in protein isoform ratios cause abnormal aggregation of tau and neurodegeneration. Pathological tau causes neuronal loss in Alzheimer's disease (AD) and a diverse group of disorders called the frontotemporal dementias (FTD), which are two of the most common forms of dementia and afflict more than 10% of the elderly population. Autosomal dominant mutations in the tau gene cause frontotemporal dementia with parkinsonism-chromosome 17 type (FTDP-17). Just over half the mutations affect tau protein function and decrease its affinity for microtubules (MTs) or increase self-aggregation. The remaining mutations occur within exon 10 (E10) and intron 10 sequences and alter complex regulation of E10 splicing by multiple mechanisms. FTDP-17 splicing mutations disturb the normally balanced levels of distinct protein isoforms that result in altered biochemical and structural properties of tau. In addition to FTDP-17, altered tau isoform levels are also pathogenically associated with other FTD disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration and Pick's disease; however, the mechanisms remain undefined and mutations in tau have not been detected. FTDP-17 highlights the association between splicing mutations and the pronounced variability in pathology as well as phenotype that is characteristic of inherited disorders.

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    ABSTRACT: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term "tauopathies" for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tau in vivo, several knockout mouse strains with deletion of the tau-encoding MAPT gene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons and in vivo. Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between Aβ and tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tau in vivo.
    06/2012; 2012:873270. DOI:10.1155/2012/873270
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    ABSTRACT: A heterozygous genomic deletion removing exons 6 to 9 of the microtubule associated protein tau (MAPT) gene, predicting to result into a truncated protein lacking the first microtubule binding domain, was detected in a patient with frontotemporal dementia (FTD). Cell culture experiments showed that the truncated tau isoforms had a dramatic decrease in the normal binding to microtubules but acquired the ability to bind microtubule associated protein-1B (MAP-1B). This indicates that this tauopathy likely results both from a loss of function mechanism and from a deleterious gain of function by which cytoplasmic deleted forms of tau sequester another MAP. Both mechanisms could contribute to impair microtubule dynamics.
    Human Mutation 04/2009; 30(4):E591-602. DOI:10.1002/humu.20979 · 5.05 Impact Factor
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    ABSTRACT: Among the early changes in the brains of Alzheimer's disease patients is the loss of synapses, which is accompanied by the abnormal phosphorylation of tau protein, its missorting into the somatodendritic compartment of neurons, and its incipient aggregation. The physiological function of tau is to stabilize axonal microtubules, which enables them to carry out their role as tracks for the transport of vesicles and organelles. By implication, perturbations in the functions of tau could be related to the loss of synapses and neuronal degeneration. Cell and trans-genic animal models of tauopathy reveal that tau can indeed cause an impairment of transport in neurons. As a result, cell processes of neurons become starved, leading first to the decay of synapses and then to the loss of axons and dendrites.
    02/2009: pages 59-70;


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