Genetic analysis of MAPT haplotype diversity in frontotemporal dementia

The H1 haplotype of the tau gene, MAPT, has been linked to the sporadic tauopathies corticobasal degeneration and progressive supranuclear palsy; however, there have been inconsistent findings regarding association with frontotemporal dementia (FTD). We investigated MAPT haplotype diversity, in 171 sporadic FTD and 186 healthy controls individuals, and report no single marker or haplotype association with increased risk or changes in age at onset. These findings do not support an association of MAPT with FTD but do not rule out its association with other tauopathies.     

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at θ = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of −2.79, and −2.27 at θ = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease. Am. J. Med. Genet. 74:380–385, 1997. © 1997 Wiley-Liss, Inc.     

Progranulin locus deletion in frontotemporal dementia

Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.     

The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies

The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of β amyloid (Aβ). Recent in vitro studies have shown that Aβ can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1α (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tau pathology or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from Aβ deposits. Our findings provide new pathological insight into the close association between p-tau and UPR activation in tauopathies.     

Microtubule-associated protein tau genetic variations are uncommon cause of frontotemporal dementia in south India

Microtubule-associated protein tau (MAPT) positive neuropathology is the characteristic feature of majority of frontotemporal dementia (FTD) cases, which is due to the mutations or haplotypic variations in the gene encoding MAPT (MAPT). The present study was aimed at determining the frequency of genetic variations in MAPT in a south Indian FTD cohort. The frequency of mutations were determined in 116 FTD, 8 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS) patients and haplotype diversity were analyzed in a study cohort comprising 116 FTD, 8 PSP, 3 CBS, 194 other dementia groups, 78 mild cognitive impairment (MCI) and 130 cognitively normal individuals and report no pathogenic mutations in FTD/PSP/CBS or haplotypic association with disease risk in FTD or other dementia patients. These findings suggest that there may be other genetic or epigenetic factors contributing to the pathogenesis of FTD in the south Indian population.     

Relevance of host tau in tau seeding and spreading in tauopathies

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild‐type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age‐related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging‐related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl‐insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre‐tangles. A percentage of intracellular tau deposits co‐localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.     

Distribution of tau hyperphosphorylation in canine dementia resembles early Alzheimer’s disease and other tauopathies

Some aged community dogs acquire a degenerative syndrome termed Canine Cognitive Dysfunction (CCD) that resembles human dementia because of Alzheimer’s Disease (AD), with comparable cognitive and behavioral deficits. Dogs also have similar neuroanatomy, share our domestic environment and develop amyloid‐β plaques, making them likely a valuable ecological model of AD. However, prior investigations have demonstrated a lack of neurofibrillary tau pathology in aged dogs, an important hallmark of AD, though elevated phosphorylated tau (p‐tau) at the Serine 396 (S396) epitope has been reported in CCD. Here using enhanced immunohistochemical methods, we investigated p‐tau in six CCD brains and six controls using the AT8 antibody (later stage neurofibrillary pathology), and an antibody against S396 p‐tau (earlier stage tau dysfunction). For the first time, we systematically assessed the Papez circuit and regions associated with Braak staging and found that all CCD dogs displayed elevated S396 p‐tau labeling throughout the circuit. The limbic thalamus was particularly implicated, with a similar labeling pattern to that reported for AD neurofibrillary pathology, especially the anterior nuclei, while the hippocampus exhibited dysfunction confined to synaptic layers and efferent pathways. The cingulate and temporal lobes displayed significantly greater tauopathy than the frontal and occipital cortices, also reflective of early Braak staging patterns in AD. Immunofluorescence confirmed that S396 was accumulating within neuronal axons, somata and oligodendrocytes. We also observed AT8 labeling in one CCD brain, near the transentorhinal cortex in layer II neurons, one of the first regions to be affected in AD. Together, these data demonstrate a concordance in regional distribution of tauopathy between CCD and AD, most evident in the limbic thalamus, an important step in further validating CCD as a translational model for human AD and understanding early AD pathogenic mechanisms.     

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update

Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.     

The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.     

The neuropathology of neurodegenerative diseases causing dementia

The dementia syndrome is increasing in prevalence throughout the developed world as the population ages. For example, in the United States it is estimated that between 2000 and 2020, the number of people living to 100 years or more will increase by over 200%, and the number of people surviving to 90–95 years will double. Based on these and other epidemiologic data, the prevalence of diseases causing the dementia syndrome has and will continue to increase dramatically over the next several decades. Considering Alzheimer's disease alone, the most common cause of dementia in the elderly, there are currently 5.5 million persons affected in the United States, and that prevalence will increase to 16 million by the first half of this century. This review will focus on the histopathology of important neurodegenerative diseases of the brain that cause dementia, including Alzheimer's disease, frontotemporal lobar degenerations, and dementia with Lewy bodies. In addition, a less common but extraordinarily interesting condition, chronic traumatic encephalopathy, will be reviewed.     

Progranulin null mutations in both sporadic and familial frontotemporal dementia

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.     

Octapeptide repeat alteration mutations of the prion protein gene in clinically diagnosed Alzheimer's disease and frontotemporal dementia

Studies focusing on octapeptide repeat alteration mutations in PRNP in Alzheimer's disease (AD) and frontotemporal dementia (FTD) cohorts have been rare. We aim to screen sporadic AD and FTD patients with unknown etiology for the octapeptide repeat insertions and deletions in PRNP. Two hundred and six individuals were screened for alterations to the repeat region in the PRNP gene, including 146 sporadic AD and 60 sporadic FTD patients. Our study showed a 1.5% (3/206) occurrence of the octapeptide repeat alteration mutations in PRNP in a Chinese cohort of sporadic dementia. One late-onset FTD patient and one early-onset AD patient each had a two-octapeptide repeat deletion in PRNP, while one early-onset AD patient had a five-octapeptide repeat insertion mutation. PRNP octapeptide repeat alteration mutations are present in sporadic AD and FTD patients. The genetic investigation for PRNP octapeptide repeat alteration mutations in sporadic dementia patients should be carried out in future clinical studies.     

Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling

The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult-onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline.     

N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from β-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy–thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

蛋白磷酸酯酶在Alzheimer氏病tau蛋白异常磷酸化中的作用

用蛋白磷酸酯酸PP-2A、-2B和-1型分别处理的Alzheimer病（AD）异常磷酸化tau蛋白可不同程度恢复其促微管聚集和组装功能。PP－2A的恢复作用比PP－2B和PP－1更强．PP－2A,PP－2B和PP－1使异常tau蛋白水解释放磷酸的量分别为其总量的57％,36％和30％。tau蛋白Ser－235位的磷酸化不是决定其功能的关键位点,而Thr－231的磷酸化可能与微管组装早期的成核聚集作用有关。该研究证明：体内蛋白磷酸酯酶PP－2A,PP－2B和PP－1可能参与tau蛋白异常磷酸化过程,保持这些磷酸酯酶的活性有可能抑制AD神经原纤维退化．     

Aging‐related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes

Aging‐related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau‐bearing astrocytes: thorn‐shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old‐aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau‐C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl‐insoluble fractions reveal a pattern of phospho‐tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen in AD. Phosphoproteomics of dissected vulnerable regions identifies an increase of phosphorylation marks in a large number of proteins in ARTAG compared with controls. GFAP, aquaporin 4, several serine‐threonine kinases, microtubule associated proteins and other neuronal proteins are among the differentially phosphorylated proteins in ARTAG thus suggesting a hyper‐phosphorylation background that affects several molecules, including many kinases and proteins from several cell compartments and various cell types. Finally, present results show for the first time that tau seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type mice of sarkosyl‐insoluble fractions enriched in hyper‐phosphorylated tau from selected ARTAG cases. These findings show astrocytes as crucial players of tau seeding in tauopathies.     

tau蛋白在老年性痴呆症神经原纤维退行性变中的作用

对老年性痴呆症发病的分子机理的研究在近20余年取得了很大进展,其中一个里程碑式的发现就是阐明了高度磷酸化的微管相关蛋白tau为组成病理性双螺旋细丝的主要蛋白成分。进一步研究显示tau的过度磷酸化在以tau异常沉积于神经元中为特征的神经原纤维退行性病变中起关键作用。由于神经原纤维退行性病变与老年性痴呆症的痴呆症状直接相关,文章综述并讨论了tau蛋白、tau过度异常磷酸化及其形成机理,并在此基础上提出了老年性痴呆症神经原纤维退行性病变的分子机理。     

Replication of GWAS associations for GAK and MAPT in Parkinson's disease

In the investigation of disease aetiology, the genome-wide association study (GWAS) provides a hypothesis-free investigation of the broader human genome and, as with all scientific investigations, replication is essential to validate any findings. To date, six GWAS have been performed to investigate the influence of common genetic variation in Parkinson's disease (PD) and only two associations have been replicated: alpha synuclein (SNCA) and microtubule-associated protein tau (MAPT), both PD candidate genes before GWAS. In our population-based study, we genotyped four of the top single-nucleotide polymorphisms (SNPs) from a previous study. By using the identical analytic method and genetic model in our independent sample, we provide evidence for replication of rs1724425 near MAPT (OR = 0.74, P= 0.0163) and rs1564282 in cyclin G-associated kinase (GAK; OR = 1.61, P= 0.0151); rs3775478 of multimerin 1 (MMRN1) (P= 0.30) and rs356229 of SNCA (P= 0.14) did not replicate in our study population. While MAPT has been considered a PD candidate gene and has been observed in association with PD in other GWAS, GAK is a new candidate for investigation in future studies.     

Frontal asymmetry in behavioral variant frontotemporal dementia: clinicoimaging and pathogenetic correlates

We aimed to assess associations between clinical, imaging, pathologic, and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial, and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into 3 groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared with left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.