Figure 1 - uploaded by Bernardino Francesco Ghetti
Content may be subject to copyright.
MAPT and the six tau isoforms expressed in adult human brain and mutations in MAPT in frontotemporal dementia and parkinsonism linked to chromosome 17. (A) MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green), and E10 (yellow) gives rise to six tau isoforms (352-441 amino acids). The constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, E13) are indicated in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is only expressed in the peripheral nervous system. The repeats of tau (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). Each repeat is 31 or 32 amino acids in length. (B) Shown are 39 coding region mutations in E1, E9, E10, E11, E12, and E13 as well as seven intronic mutations flanking E10.
Source publication
Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are...
Contexts in source publication
Context 1
... pro- tein that stabilizes microtubules and promotes microtubule assembly. It followed the finding that the intracellular inclusions of Alzheimer disease stain for hyperphosphorylated tau ( Brion et al. 1985;Grundke-Iqbal et al. 1986). In adult human brain, six tau isoforms are expressed from a single MAPT gene through alternative mRNA splicing (Fig. 1A) (Goedert et al. 1989a,b). Three isoforms have three re- peats each and three isoforms have four repeats each. By 1992, the paired helical filament of Alzheimer disease had been shown to be made of the six tau isoforms, each full-length and hyperphosphorylated ( Goedert et al. 1988Goedert et al. , 1992Wischik et al. 1988;Lee et al. ...
Context 2
... in MAPT account for 5% of cases of FTD and are believed to cause disease through a gain of toxic function mechanism. Most mutations are located in exons 9-12 (which encode the repeats) and the adjacent introns (Fig. 1B). It remains to be determined whether the amino acid changes in codon 5 of exon 1 are pathogenic. Mutations fall into two largely nonoverlapping groups: those with a primary effect at the protein level and those influencing the alternative splicing of tau pre- mRNA. Mutations acting at the protein level change or delete single amino ...
Citations
... Another important aspect of thalamic pathology in MNDs is the interaction with frontotemporal dementia (FTD), a common comorbidity of MNDs [20,21]. FTD covers a group of neurodegenerative diseases affecting the frontal and temporal lobes of the brain, leading to progressive changes in behavior, language, and executive function [22,23]. FTD is classified into three main subtypes: behavioral variant FTD (bvFTD), primary progressive aphasia of the semantic variant (svPPA), and non-fluent/analogue variant PPA (nfvPPA) [24][25][26]. ...
Background: Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by motor impairment and non-motor symptoms. The involvement of the thalamus in MNDs, especially in conditions such as amyotrophic lateral sclerosis (ALS), and its interaction with frontotemporal dementia (FTD), has garnered increasing research interest. This systematic review analyzed magnetic resonance imaging (MRI) studies that focused on thalamic alterations in MNDs to understand the significance of these changes and their correlation with clinical outcomes. Methods: Following PRISMA 2020 guidelines, the PubMed and Scopus databases were searched from inception to June 2023 for studies related to MRI findings in the thalamus of patients with MNDs. Eligible studies included adult patients diagnosed with ALS or other forms of MND who underwent brain MRI, with outcomes related to thalamic alterations. Studies were evaluated for risk of bias using the Newcastle-Ottawa scale. Results: A total of 52 studies (including 3009 MND patients and 2181 healthy controls) used various MRI techniques, including volumetric analysis, diffusion tensor imaging, and functional MRI, to measure thalamic volume, connectivity, and other alterations. This review confirmed significant thalamic changes in MNDs, such as atrophy and microstructural degradation, which are associated with disease severity, progression, and functional disability. Thalamic involvement varies across different MND subtypes and is influenced by the presence of cognitive impairment and mutations in genes including chromosome 9 open reading frame 72 (C9orf72). The synthesis of findings across studies indicates that thalamic pathology is a prevalent early biomarker of MNDs that contributes to motor and cognitive deficits. The thalamus is a promising target for monitoring as its dysfunction underpins a variety of clinical symptoms in MNDs. Conclusions: Thalamic alterations provide valuable insights into the pathophysiology and progression of MNDs. Multimodal MRI techniques are potent tools for detecting dynamic thalamic changes, indicating structural integrity, connectivity disruption, and metabolic activity.
... FTD is characterized by the atrophy of the frontal and temporal lobes. FTD is characterized by various mutations that lead to the deposition of ubiquitinated TDP-43 and hyperphosphorylated tau proteins in the frontal and temporal lobes, leading to dementia, early personality, behavioral changes, and aphasia depending on the subtype 37) . Neuronal loss, microvacuolation, and myelin loss were noted 38) . ...
Dementia is an umbrella term that describes the loss of thinking, memory, attention, logical reasoning, and other mental abilities to the extent that it interferes with the activities of daily living. More than 50 million individuals worldwide live with dementia, which is expected to increase to 131 million by 2050. Recent research has shown that poor oral health increases the risk of dementia, while oral health declines with cognitive decline. Improving oral health can prevent dementia progression and improve the quality of life of patients. In this narrative review, the literature was based on the "hypothesis" that dementia and oral health have a close relationship, and appropriate oral health and occlusal rehabilitation treatment can improve the quality of life of patients with dementia and prevent progression. We conducted a literature search in PubMed and Google Scholar databases, using the search terms "dementia," "major neurocognitive disorder," "dentition," "occlusion," "tooth loss," "dental prosthesis," "dental implant," and "occlusal rehabilitation" in the title field over the past 30 years. A total of 131 studies that scientifically addressed dementia, oral health, and/or oral rehabilitation were included. In a meta-analysis, the random effect model demonstrated significant tooth loss increasing the dementia risk 3.64-fold (pooled odds ratio=3.64, 95% confidence interval [2.50~5.32], P-value=0.0348). Conversely, tooth loss can be an important indicator of cognitive function decline. As the number of missing teeth increases, the risk of dementia increases. Loss of teeth can lead to a decrease in the ascending information to the brain and reduced masticatory ability, cerebral blood flow, and psychological atrophy. Oral microbiome dysbiosis and migration of key bacterial species to the brain can also cause dementia. Additionally, inflammation in the oral cavity affects the inflammatory response of the brain and the complete body. Conversely, proper oral hygiene management helps improve the quality of life of patients with dementia. The placement of dental implants or prostheses to replace lost teeth and restore masticatory function can inhibit symptom progression in patients with dementia. Therefore, maintaining proper oral health in patients with dementia is essential to reduce symptoms and restore the quality of life.
... Cell culture and transgenic mouse models showed that reduction of tau markedly ameliorated the adverse effects resulting from Aβ accumulation [15,16]. Finally, a cohort of neurodegenerative tauopathies share the trait of the deposition of hyperphosphorylated tau, wild type or bearing a mutation, without Aβ plaques [17,18]. Transgenic overexpression of the P301S mutant tau from frontotemporal dementia with Parkinsonism-chromosome 17 [19,20] causes progressive accumulation of tau inclusions, accompanied by neuronal loss and brain atrophy in 9-12-month-old mice [21][22][23]. ...
Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer’s disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson’s disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer’s disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer’s disease drug discovery.
... Tau can possess a remarkable degree of posttranslational modification, including N-and O-glycosylation, ubiquitination, truncation, glycation, and oxidation, amounting to 63 unique posttranslational modifications that have been reported in wild-type mice [4]. Despite the diversity in posttranslational modifications, a cohort of neurodegenerative tauopathies share the trait of the deposition of hyperphosphorylated tau, whether wildtype or bearing a mutation [5,6], suggesting that abnormal phosphorylation of tau plays one of the key factors in the disease. ...
The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer’s disease.
... Cell culture and transgenic mouse models showed that reduction of tau markedly ameliorated the adverse effects resulting from Aβ accumulation [15, 16]. Finally, a cohort of neurodegenerative tauopathies share the trait of the deposition of hyperphosphorylated tau, wildtype or bearing a mutation, without Aβ plaques [17, 18]. Transgenic overexpression of the P301S mutant tau from frontotemporal dementia with Parkinsonism -chromosome 17 [19,20] causes progressive accumulation of tau inclusions, accompanied by neuronal loss and brain atrophy in 9-12 months old mice [21][22][23]. ...
Background
Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer’s disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlie neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs.
Methods
Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack.
Results
Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, Unfolded Protein Response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. P-tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson’s disease symptoms, and by overexpression of HO-1.
Conclusion
Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery.
... To this end, 10-plex TMT (tandem mass tag)-based quantitative proteomics and frozen brain tissue samples from AD patients at Braak stages IV-VI and healthy individuals and vascular (VD) and frontotemporal (FTD) dementia patients as controls were used. The prefrontal cortex of VD and FTD patients is affected in both pathologies, with these dementias either being the most common after AD or associated with young-onset dementia, respectively [29][30][31][32][33][34][35]. Moreover, abnormal protein deposits associated with AD coexist with blood vessel alterations linked with VD [31,36,37]. ...
... Moreover, abnormal protein deposits associated with AD coexist with blood vessel alterations linked with VD [31,36,37]. In contrast, FTD is one of the most common dementias associated with NFTs, characteristic of AD patients [29,37]. Thus, their use as controls would potentially allow to identify AD-associated proteins non-related to VD alterations, and other NFTs associated dementias (FTD), and to get a better understanding of the pathological mechanisms specifically associated with the development and progression of AD. ...
... Moreover, besides healthy samples, VD and FTD samples were also used as controls for the identification of proteins specifically altered in AD and non-related to VD alterations and/or NFTs associated dementias (FTD). Besides their use as controls regarding the most incident dementia after AD (VD), and young-onset dementia (FTD) [29][30][31][32][33][34][35], they should also allow, in combination with healthy individuals as controls, to get further insights into AD pathology. In addition, different AD Braak stage samples were used to identify dysregulated proteins during the course of the disease. ...
Background
Alzheimer’s disease (AD) is a progressive, chronic, and neurodegenerative disease, and the most common cause of dementia worldwide. Currently, the mechanisms underlying the disease are far from being elucidated. Thus, the study of proteins involved in its pathogenesis would allow getting further insights into the disease and identifying new markers for AD diagnosis.
Methods
We aimed here to analyze protein dysregulation in AD brain by quantitative proteomics to identify novel proteins associated with the disease. 10-plex TMT (tandem mass tags)-based quantitative proteomics experiments were performed using frozen tissue samples from the left prefrontal cortex of AD patients and healthy individuals and vascular dementia (VD) and frontotemporal dementia (FTD) patients as controls (CT). LC–MS/MS analyses were performed using a Q Exactive mass spectrometer.
Results
In total, 3281 proteins were identified and quantified using MaxQuant. Among them, after statistical analysis with Perseus (p value < 0.05), 16 and 155 proteins were defined as upregulated and downregulated, respectively, in AD compared to CT (Healthy, FTD and VD) with an expression ratio ≥ 1.5 (upregulated) or ≤ 0.67 (downregulated). After bioinformatics analysis, ten dysregulated proteins were selected as more prone to be associated with AD, and their dysregulation in the disease was verified by qPCR, WB, immunohistochemistry (IHC), immunofluorescence (IF), pull-down, and/or ELISA, using tissue and plasma samples of AD patients, patients with other dementias, and healthy individuals.
Conclusions
We identified and validated novel AD-associated proteins in brain tissue that should be of further interest for the study of the disease. Remarkably, PMP2 and SCRN3 were found to bind to amyloid-β (Aβ) fibers in vitro, and PMP2 to associate with Aβ plaques by IF, whereas HECTD1 and SLC12A5 were identified as new potential blood-based biomarkers of the disease.
... In 1985 and 1986 a series of studies described the microtubule associate protein Tau as a component of paired-helical filaments, an intracellular pathology hallmark of AD known as neurofibrillary tangles. The relevance of Tau was supported by subsequent genetic studies showing mutations in Tau were associated with neurodegenerative disease (Goedert et al., 2012). Following close upon these discoveries was the identification of the gene that encoded amyloid-sequestered peptides, Amyloid Precursor Protein (APP) (Goldgaber et al., 1987;Kang et al., 1987;Tanzi et al., 1987). ...
Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer’s disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.
... Furthermore, there are reports which suggest that p-tau re-locates to the nuclear membrane, interacts with the NPC, and inhibits nucleus-cytosol transports in tau transgenic mice and AD brain 39 , thereby resulting in cytoplasmic aggregates, which comprise of phosphorylated tau and nuclear pore proteins in neurons with neurofibrillary tangles (NFTs) 39 . In addition, autosomal dominant missense as well as splicing mutation in MAPT cause microtubule mediated deformation of the nucleus in inherited frontotemporal dementia (FTD) [40][41][42] . Several studies have reported the involvement of DSB in tau pathology. ...
DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer’s disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy. Phosphorylated microtubule-associated protein tau (p-tau) accumulates at double-strand breaks (DSBs) in neurons. Loss of tau induces failure of DSB repair and excessive DSB accumulation, leading to aberrant p-tau aggregation and apoptotic neurons.
... soluble TREM2 j amyloid-β j Alzheimer's disease j integrative modeling j fibrillization kinetics A lzheimer's disease (AD) is the most common form of dementia and features the neuropathological hallmarks of extracellular Aβ plaques and intraneuronal tau neurofibrillary tangles (1,2). Human genetic studies on heritable mutations in APP and PSEN causing early-onset familial AD (3) argue that pathogenic Aβ drives tau neurofibrillary tangle formation; in contrast, mutations in MAPT do not lead to Aβ pathology nor cause AD, but rather a rare genetic form of early-onset primary tauopathy (4). In support of the molecular genetics, a recent cross-sectional study in postmortem human AD brain samples demonstrated the presence and correlation of robust prion bioactivity for Aβ and tau proteins in nearly all cases (5), suggesting that even at death, Aβ in prion conformations are active in the late stages of disease. ...
Significance
Mutations in a microglial protein, TREM2, represents a risk for Alzheimer’s disease (AD). We show that the soluble form of TREM2, sTREM2, can bind and inhibit fibrillization of Aβ peptides. sTREM2 increases uptake of Aβ fibrils into microglial and neuroglioma cell lines. Contrastingly, mutation R47H was found to have little effect on fibril nucleation and binding, but decreased uptake and functional responses. Our findings using integrative molecular modeling based on cross-linking mass spectrometry data for WT sTREM2–Aβ fibril complex demonstrate that TREM2 has at least two ligand-binding surfaces: one binding Aβ fibrils and the other anionic polyvalent ligands. R47H mutation lies on the latter surface. These findings inform mechanisms by which TREM2 modulates key processes in AD progression.
... While inherited cases of frontotemporal dementia with parkinsonism linked to chromosome 17 emphasize the importance of pathological tau as one of the main causes of "primary tauopathies" (21)(22)(23), the association of aberrantly modified tau with the clinical and neuropathologic etiology of "secondary tauopathies" (e.g., Niemann-Pick disease type C, traumatic brain injury, and chronic traumatic encephalopathy) is more loose and mainly correlated to the presence of neuronal and/or astrocytic tau aggregates in certain brain areas (2,17). Based on familial cases of frontotemporal dementia with parkinsonism linked to chromosome 17, Pick's diseases, corticobasal degeneration, and progressive supranuclear palsy (24,25), disease-causing mutations in the MAPT (MAP tau) gene lead to heterogeneous molecular consequences. In this regard, most tau variants exhibit a higher tendency to form insoluble filaments and have different affinities for interacting partners or subcellular structures (e.g., microtubule, plasma membrane). ...
Microtubule-associated protein tau is a naturally unfolded protein that can modulate a vast array of physiological processes through direct or indirect binding with molecular partners. Aberrant tau homeostasis has been implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer’s disease (AD). In this study, we performed an unbiased high-content protein profiling assay by incubating recombinant human tau on microarrays containing thousands of human polypeptides. Among the putative tau-binding partners, we identify S-adenosylhomocysteine hydrolase-like protein 1/ inositol 1,4,5-trisphosphate receptor (IP3R) binding protein (AHCYL1/IRBIT), a member of the S-adenosylhomocysteine hydrolase family and a previously described modulator of IP3R activity. Using co-immunoprecipitation assays, we show that endogenous as well as overexpressed tau can physically interact with AHCYL1/IRBIT in brain tissues and cultured cells. Proximity ligation assay (PLA) experiments demonstrate that tau overexpression may modify the close localization of AHCYL1/IRBIT to IP3R at the endoplasmic reticulum (ER). Together, our experimental evidence indicates that tau interacts with AHCYL1/IRBIT and potentially modulates AHCYL1/IRBIT function.
