Tau is central in the genetic Alzheimer–frontotemporal dementia spectrum

Department of Molecular Genetics (VIB 8), Flanders Interuniversity Institute for Biotechnology, Neurodegenerative Brain Diseases Group, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
Trends in Genetics (Impact Factor: 9.92). 01/2006; 21(12):664-72. DOI: 10.1016/j.tig.2005.09.005
Source: PubMed


In contrast to the common and genetically complex senile form of Alzheimer's disease (AD), the molecular genetic dissection of inherited presenile dementias has given important mechanistic insights into the pathogenesis of degenerative brain disease. Here, we focus on recent genotype-phenotype correlative studies in presenile AD and the frontotemporal dementia (FTD) complex of disorders. Together, these studies suggest that AD and FTD are linked in a genetic spectrum of presenile degenerative brain disorders in which tau appears to be the central player.

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    • "Here, we review the contribution of Drosophila to the molecular understanding of Tau neurotoxicity, a central player in the AD-FTD spectrum of disorders [9]. We give a brief overview of the most commonly used genetic tools in Drosophila and summarize the different available Tau models and readouts for Tau neurotoxicity. "
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    ABSTRACT: Aggregates of the microtubule-associated protein Tau are neuropathological hallmark lesions in Alzheimer's disease (AD) and related primary tauopathies. In addition, Tau is genetically implicated in a number of human neurodegenerative disorders including frontotemporal dementia (FTD) and Parkinson's disease (PD). The exact mechanism by which Tau exerts its neurotoxicity is incompletely understood. Here, we give an overview of how studies using the genetic model organism Drosophila over the past decade have contributed to the molecular understanding of Tau neurotoxicity. We compare the different available readouts for Tau neurotoxicity in flies and review the molecular pathways in which Tau has been implicated. Finally, we emphasize that the integration of genome-wide approaches in human or mice with high-throughput genetic validation in Drosophila is a fruitful approach.
    International Journal of Alzheimer's Disease 06/2012; 2012(5530):970980. DOI:10.1155/2012/970980
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    • "Thus, understanding the nature of attention deficits in early AD may provide insights into the mechanisms that dissociate AD from normal aging. Mutations in genes encoding β-amyloid precursor protein (APP) or presenilin 1 lead to inherited, early onset forms of AD (Haass 1997, Selkoe 1998), and mutations in the microtubule-associated protein tau cause some cases of frontotemporal lobe dementia (Dermaut et al., 2005). Transgenic mice overexpressing these altered human genes develop age-dependent learning and memory deficits, thus mimicking important behavioural aspects of the disease (Götz and Ittner 2008). "
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    ABSTRACT: Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2011; 31(9):3500-7. DOI:10.1523/JNEUROSCI.5242-10.2011 · 6.34 Impact Factor
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    • "A number of neurodegenerative disorders are caused by mutations in genes expressed principally in the central nervous system. This is the case for the brain proteins tau and α-synuclein, which are genetically linked to autosomal dominant forms of frontotemporal dementia [214] and PD [215], respectively. Recently, we postulated that susceptibility to AD could come from genes predominantly expressed in affected brain regions, such as the hippocampus. "
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    ABSTRACT: Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival. Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer's disease, provides strong support for a role of calcium in neurodegeneration. These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.
    Molecular Neurodegeneration 06/2009; 4(1):20. DOI:10.1186/1750-1326-4-20 · 6.56 Impact Factor
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