We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro.
We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted.
We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer's disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene.
We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10(-4)) with the inversion polymorphism containing MAPT.
We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene.
We genotyped all family members for microsatellite markers at the IBGC1 locus and polymorphisms of the ApoE, VLDL, alpha1-ACT, BChE-K, APP, PS1, PS2 and tau genes and tested these for linkage to IBGC, dementia and bipolar disorder.
Two of these more broadly expressed gene family members, LRRC37A1 and A4, define the boundary of a common human inversion polymorphism mapping to chromosome 17q21.31 (the MAPT locus)-a region associated with risk for frontal temporal dementia, Parkinsonism, and intellectual disability.
Twenty years ago, we and others showed that mutations in MAPT, the Tau gene, cause familial forms of frontotemporal dementia, thus proving that dysfunction of Tau protein is sufficient to cause neurodegeneration and dementia.
Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Aβ and p-tau proteins.
To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD).
Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family.
This study is a reappraisal of the strong association of APOE variability with AD in southern India when compared to other dementia groups, while the transcriptional differences between MAPT haplotypes have a limited role in Indian dementia patients.
The transition of tau proteins from its soluble physiological conformation to the pathological aggregate forms found in Alzheimer's disease and related dementias, is poorly understood.
The polymorphism of apolipoprotein E (apoE) has been recognized as a genetic risk factor in different neurodegenerative disorders, with or without tau protein- related neuropathology, but few published epidemiological data are available as concerns the association of different apoE alleles with two relatively rare forms of dementia, Pick's disease (PiD) and Huntington's disease (HD).
The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau.
The identification of mutations in Tau as the cause of FTDP-17 established that dysfunction or misregulation of tau protein is sufficient to cause neurodegeneration and dementia.
The identification of mutations in MAPT, the gene that encodes tau, causing dementia and parkinsonism established the notion that tau aggregation is responsible for the development of disease.