ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.

Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidate cis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduced MAPT expression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates.

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate-like density for nuclear-envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

Proximity labeling reveals dynamic changes in the SQSTM1 protein network.

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and of the relationship of the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

Tau reduction with artificial microRNAs modulates neuronal physiology and improves tauopathy phenotypes in mice.

Abnormal tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies aimed at reducing tau in the brain are promising therapeutic interventions, yet more precise therapies would require targeting specific nuclei and neuronal subpopulations affected by disease while avoiding global reduction of physiological tau. Here, we developed artificial microRNAs directed against the human MAPT mRNA to dwindle tau protein by engaging the endogenous RNA interference pathway. In human differentiated neurons in culture, microRNA-mediated tau reduction diminished neuronal firing without affecting neuronal morphology or impairing axonal transport. In the htau mouse model of tauopathy, we locally expressed artificial microRNAs in the prefrontal cortex (PFC), an area particularly vulnerable to initiating tau pathology in this model. Tau knockdown prevented the accumulation of insoluble and hyperphosphorylated tau, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in the PFC. Moreover, such tau reduction prevented cognitive decline in aged htau mice. Our results suggest target engagement of designed tau-microRNAs to effectively reduce tau pathology, providing a proof of concept for a potential therapeutic approach based on local tau knockdown to rescue tauopathy-related phenotypes.

iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death.

BACKGROUND: Tau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick's disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies. METHODS: To understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons. RESULTS: FTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases. CONCLUSIONS: Our results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions.

Role of autophagy-related genes in liver cancer prognosis.

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.

Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation.

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.

Pathologic correlates of aging-related tau astrogliopathy: ARTAG is associated with LATE-NC and cerebrovascular pathologies, but not with ADNC.

Age-related tau astrogliopathy (ARTAG) is detectable in the brains of over one-third of autopsied persons beyond age 80, but the pathoetiology of ARTAG is poorly understood. Insights can be gained by analyzing risk factors and comorbid pathologies. Here we addressed the question of which prevalent co-pathologies are observed with increased frequency in brains with ARTAG. The study sample was the National Alzheimer's Coordinating Center (NACC) data set, derived from multiple Alzheimer's disease research centers (ADRCs) in the United States. Data from persons with unusual conditions (e.g. frontotemporal dementia) were excluded leaving 504 individual autopsied research participants, clustering from 20 different ADRCs, autopsied since 2020; ARTAG was reported in 222 (44.0%) of included participants. As has been shown previously, ARTAG was increasingly frequent with older age and in males. The presence and severity of other common subtypes of pathology that were previously linked to dementia were analyzed, stratifying for the presence of ARTAG. In logistical regression-based statistical models that included age and sex as covariates, ARTAG was relatively more likely to be found in brains with limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and in brains with comorbid cerebrovascular pathology (arteriolosclerosis and/or brain infarcts). However, ARTAG was not associated with severe Alzheimer's disease neuropathologic change (ADNC), or primary age-related tauopathy (PART). In a subset analysis of 167 participants with neurocognitive testing data, there was a marginal trend for ARTAG pathology to be associated with cognitive impairment as assessed with MMSE scores (P = 0.07, adjusting for age, sex, interval between final clinic visit and death, and ADNC severity). A limitation of the study was that there were missing data about ARTAG pathologies, with incomplete operationalization of ARTAG according to anatomic region and pathologic subtypes (e.g., thorn-shaped or granular-fuzzy astrocytes). In summary, ARTAG was not associated with ADNC, whereas prior observations about ARTAG occurring with increased frequency in aging, males, and brains with LATE-NC were replicated. It remains to be determined whether the increased frequency of ARTAG in brains with comorbid cerebrovascular pathology is related to local infarctions or neuroinflammatory signaling, or with some other set of correlated factors including blood-brain barrier dysfunction.

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers.

While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

Parkinson-ALS with a novel MAPT variant.

The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.

Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity.

INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored. RESULTS: Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3. DISCUSSION: Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers.

The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes.

INTRODUCTION: Alternative splicing of the human MAPT gene generates six brain-specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations. METHODS: A comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server. RESULTS: While TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive. DISCUSSION: In this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU-associated diseases. HIGHLIGHTS: MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development-, cell-type and brain region specific. The contribution of TAU to neurodegeneration might be isoform-specific. Ineffective TAU-based therapies highlight the need for specific targeting strategies.

Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.

BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.

Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.

INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible. METHODS: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs. RESULTS: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant.

Mutational Landscape of Alzheimer's Disease and Frontotemporal Dementia: Regional Variances in Northern, Central, and Southern Italy.

Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) are the two major neurodegenerative diseases with distinct clinical and neuropathological profiles. The aim of this report is to conduct a population-based investigation in well-characterized APP, PSEN1, PSEN2, MAPT, GRN, and C9orf72 mutation carriers/pedigrees from the north, the center, and the south of Italy. We retrospectively analyzed the data of 467 Italian individuals. We identified 21 different GRN mutations, 20 PSEN1, 11 MAPT, 9 PSEN2, and 4 APP. Moreover, we observed geographical variability in mutation frequencies by looking at each cohort of participants, and we observed a significant difference in age at onset among the genetic groups. Our study provides evidence that age at onset is influenced by the genetic group. Further work in identifying both genetic and environmental factors that modify the phenotypes in all groups is needed. Our study reveals Italian regional differences among the most relevant AD/FTD causative genes and emphasizes how the collaborative studies in rare diseases can provide new insights to expand knowledge on genetic/epigenetic modulators of age at onset.

Neolithic expansion and the 17q21.31 inversion in Iberia: an evolutionary approach to H2 haplotype distribution in the Near East and Europe.

The chromosomal region 17q21.31 harbors a 900 kb inversion polymorphism named after the microtubule-associated protein tau (MAPT) gene. Since no recombination occurs, two haplotypes are recognized: a directly oriented variant (H1) and an inverted variant (H2). The H2 haplotype features a distribution pattern with high frequencies in the Near East and Europe, medium levels in South Asia and North Africa, and low levels elsewhere. Studies of this genomic region are relevant owing to its likely association with numerous neurodegenerative diseases. However, the causes underlying the geographic distribution of the haplotype frequencies remain a bone of contention among researchers. With this work, we have intended to outline a plausible hypothesis on the origin of the high European H2 frequencies. To that end, we have analyzed an extensive population database (including three new Iberian populations) to explore potential clinal variations of H2 frequencies. We found a sigmoidal frequency cline with an upward trend from South Asia to Europe. The maximum value was detected in the Basques from Gipuzkoa province (0.494) with the curve's inflection point in the Near East. From our results, we suggest that the most likely scenario for high H2 frequencies in Europe would be a founding event in the Near East during the late Paleolithic or early Neolithic. Subsequently, such H2 overrepresentation would have reached Europe with the arrival of the first Neolithic farmers. The current frequencies and geographic distribution of the 17q21.31 inversion suggest that the founding events mainly affected the H2D subhaplotype.

Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy.

Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau.

Mutation ∆K281 in MAPT causes Pick's disease.

Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick's disease. We conclude that MAPT mutation ∆K281 causes Pick's disease.