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Structure of the microtubule associated protein tau. (A) The schematic representation of the longest transcript of the MAPT gene. The MAPT mRNA is composed of 14 exons and two UTRs (16 in total) which are alternatively spliced producing 9 different isoforms. MAPT gene encodes for 4 MT-binding domains (R1-R4). The R2 MT-domain is encoded by exon 11 which is alternatively spliced between different protein isoforms and is missing in fetal tau. (B) 9 different tau protein isoforms. Fetal-tau is the only isoform expressed in fetal brain tissue. (C) MAPT gene is expressed in high levels in the all areas of cerebral cortex from the earliest period during entire life (see color code and heat map). The peak expression of fetal tau is during mid-fetal period, with slight decline in expression until birth and decrease after 6th postnatal month. Data for the construction of MAPT mRNA and protein isoforms were obtained from RefSeq ID: NM 001123066.3 and UniProt ID: P10636, while expression data for MAPT transcripts were obtained from the database published in Kang et al. 2011 Abbreviations: OFC-orbital prefrontal cortex, DFC-dorsolateral prefrontal cortex, VFC-ventrolateral prefrontal cortex, MFC-medial prefrontal cortex, M1C-primary motor cortex, S1C-primary somatosensory cortex, IPC-posterior inferior parietal cortex, A1C-primary auditory cortex, STC-superior temporal cortex, ITC-inferior temporal cortex, V1C-primary visual cortex, PCW-postconception weeks.
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While early 1990s reports showed the phosphorylation pattern of fetal tau protein to be similar to that of tau in paired helical filaments (PHF) in Alzheimer's disease (AD), neither the molecular mechanisms of the transient developmental hyperphosphorylation of tau nor reactivation of the fetal plasticity due to re-expression of fetal protein kinas...
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... domains, and interact with other tau molecules, while the remain- der of the protein retains largely unfolded structure and gives rise to the fuzzy coat of the filaments ( Mandelkow et al., 2007). The human tau protein is encoded by the MAPT gene that comprises 16 exons (14 coding), located on chromosome 17q21 (RefSeq ID: NM 001123066.3, Fig. 1). The alternative splicing of exons 2, 3, and 11 of tau mRNA creates nine protein isoforms (UniProt ID: P10636, MAPT gene is expressed in high levels in the all areas of cerebral cortex from the earliest period during entire life (see color code and heat map). The peak expression of fetal tau is during mid-fetal period, with slight ...
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... prefrontal cortex, VFC -ventrolateral prefrontal cortex, MFC -medial prefrontal cortex, M1C -primary motor cortex, S1C -primary somatosensory cortex, IPC -posterior inferior parietal cortex, A1C -primary auditory cortex, STC -superior temporal cortex, ITC -inferior temporal cortex, V1C -primary visual cortex, PCW-postconception weeks. Fig. 1), which differ in the number of MT-binding domains (R3-R4) of 31-32 aa in the carboxy-terminal half (coded by exons 10-13), and in the number of amino-terminal inserts (N0-N2) of 29 or 59 aa (coded by exons 2 and 3). This results in a total number of aa ranging from 316 to 776 depending on the isoform. The adult human brain expresses ...
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... MAPT transcript is highly expressed during the entire lifes- pan in all areas and regions of the cerebral cortex ( Fig. 1, Kang et al., 2011). The most prominent expression is observed during fetal development, when only fetal tau (N0R3) is expressed. The peak of expression is in the midgestation period and for the frontal region lasts until birth (Fig. 1C). After the sixth postnatal month, 2-fold decrease in the expression levels of the MAPT transcript ...
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... transcript is highly expressed during the entire lifes- pan in all areas and regions of the cerebral cortex ( Fig. 1, Kang et al., 2011). The most prominent expression is observed during fetal development, when only fetal tau (N0R3) is expressed. The peak of expression is in the midgestation period and for the frontal region lasts until birth (Fig. 1C). After the sixth postnatal month, 2-fold decrease in the expression levels of the MAPT transcript can be observed. Although there are no significant differences in MAPT transcript expression levels among areas and regions in the human cerebral cortex, it should be noted that the peak expression is pro- longed in the frontal brain ...
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... (Fig. 1C). After the sixth postnatal month, 2-fold decrease in the expression levels of the MAPT transcript can be observed. Although there are no significant differences in MAPT transcript expression levels among areas and regions in the human cerebral cortex, it should be noted that the peak expression is pro- longed in the frontal brain region (Fig. 1C). The rate of tau protein synthesis is differentially regulated during development. Namely, tau synthesis during neurite development is local in the distal part of the axon. For example, in the mouse cerebellum, after axonal growth ends on the 20th postnatal day, only a limited number of new tau molecules are synthesized (Vilá-Ortiz et ...
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The formation of intraneuronal fibrillar inclusions of tau protein is associated with several neurodegenerative diseases referred to as tauopathies including Alzheimer's disease (AD). A common feature of these pathologies is hyperphosphorylation of tau, the main component of fibrillar assemblies such as Paired Helical Filaments (PHFs). O-β-linked N...
Citations
... Along with Aβ plaques, the other classic pathological hallmark of AD, NFTs, are composed of phosphorylated tau [56]. The normal biological function of tau is the assembly and stabilization of microtubules to regulate neuritic growth [39]. Hyper-phosphorylation of tau results in the loss of physiological function and its aggregation in select brain regions, which contributes to learning and memory impairments reported in various tauopathies [54,56]. ...
... NFTs develop by the forties and are linked to the cognitive impairment in DS [34,52,70,71]. The shortest tau isoform is highly expressed throughout fetal development, but particularly during midgestation [39]. The normal biological function of tau involves the assembly and stabilization of microtubules to regulate neuritic growth [39]. ...
... The shortest tau isoform is highly expressed throughout fetal development, but particularly during midgestation [39]. The normal biological function of tau involves the assembly and stabilization of microtubules to regulate neuritic growth [39]. Phosphorylation of fetal tau occurs in the distal portion of growing axons, which is downregulated after 35 wk gestation [39]. ...
Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ 1–42 ) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.
... The shortest transcript of tau termed fetal tau or N0R3 is found in both the normal and DS fetal brain during development [72]. N0R3 is phosphorylated around Ser202 and detected in long axonal tracts, peaking in the human brain at mid-gestation [26,73]. In fact, prenatal tau was associated with axonal guidance, particularly with axonal growth and targeting [74], which is downregulated prior to birth in humans [26]. ...
Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ1–42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.
... MAPT splicing is heavily developmentally regulated, with only the smallest isoform (0N3R) expressed during fetal brain development (Goedert and Jakes, 1990; Wang and Mandelkow, 2015). The reasons for this developmental regulation are not fully understood, although the current consensus revolves around 0N3R tau having a lower affinity for microtubule binding thus allowing enhanced cytoskeletal plasticity, something required for guiding and growing immature neurons during development (Jovanov-Milošević et al., 2012;Qiang et al., 2018). ...
... Questions have been raised about how this correlation might be related to hyperphosphorylated disease relevant tau species, and how developing brain tissue is able to contend with these high levels of tau phosphorylation Jovanov-Milošević et al., 2012;Hefti et al., 2019). Interestingly hibernating rodents, specifically arctic ground squirrels, have been shown to have high levels of tau phosphorylation (Su et al., 2008). ...
... Tau phosphorylation is important for neuronal development, in the regulation of the microtubule binding function of tau, as well as in the development of tau pathology (Kenessey and Yen, 1993;Jovanov-Milošević et al., 2012). We examined 5 phospho-sites (S199, T181, S202 and T205, S396, and S396 and S404) using phospho-specific antibodies on western blot, at 100 and 300 DIV (chapter 4). ...
https://discovery.ucl.ac.uk/id/eprint/10122129/
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Insoluble, hyper-phosphorylated aggregates of tau are a pathological hallmark of a range of clinically diverse neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the most common. The mechanisms linking neuronal death and tau dysfunction are not fully understood, but mutations uncovered in microtubule associated protein tau (MAPT) that cause aggressive frontotemporal dementia confirm a causative relationship between tau dysfunction and neurodegeneration. The tau protein exists as multiple protein isoforms in the adult human central nervous system (CNS), generated by alternative splicing of the MAPT gene. Disruptions to tau splicing are associated with a number of tauopathies, however, in vitro and in vivo models to understand the consequences of disrupted tau splicing have been lacking, due in part to species differences in tau splicing and the developmental regulation of tau in human neurons. Recently, the development of induced pluripotent stem cells (iPSC) has enabled the derivation of limitless numbers of human neurons with disease associated mutations of interest. The use of this system to model tauopathy has been challenging, in part due to the developmental regulation of tau splicing, with extended culture periods required for mature tau expression in iPSC derived neurons. Cerebral organoids are 3D based iPSC derived neuronal cultures, which help capture the heterogeneity and key aspects of architecture of the developing brain, such as distinct progenitor zones and lamination of neurons into distinct layers. We hypothesised that this may allow neurons to mature at a faster rate, resulting in earlier expression of all 6 isoforms of tau without extensive culture times. We investigated the utility of iPSC-derived cerebral organoids to model key aspects of tau biology. Cerebral organoids showed high variability in neuronal content and tau expression. To reduce this heterogeneity, we generated engineered cerebral organoids (enCORs), which utilise a floating scaffold to increase the efficiency of neural induction and reduce heterogeneity. We show that enCORs provide a robust and reproducible in vitro system for the analysis of tau expression and splicing in a 3D model. To investigate the effect of tau mutations, we generated enCORs from an isogenic series of iPSC with the MAPT 10+16 and P301S mutations. The presence of tau splicing mutations results in disease-associated alterations in tau expression, specifically a dose-dependent increase in 4R tau isoforms in the presence of the MAPT 10+16 variant. While the developmental regulation of tau splicing is conserved, maturation of tau splicing is accelerated in 3D cultures compared to 2D cultures. Finally, enCORs with coding mutations in MAPT are able to produce seed-competent tau species, suggesting enCORs recapitulate early features of tau pathology. In summary, enCORs provide a novel, robust in vitro system for the study of tau in development and disease.
... This is an important point to consider since the pattern of tau isoforms is differently regulated in fetal and adult human brains. Only the smallest tau isoform is present in fetal brain whereas all 3R and 4R tau isoforms are found in the adult brain at a ratio of 1:1 (2,55,(58)(59)(60). In rodents, a switch from 3R to 4R is observed during the development resulting in the sole presence of 4R isoforms in adult brain (55,58,60,61). ...
Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau is correlated to its redistribution from the axon to the somato-dendritic compartment at early stages of tauopathies. Interestingly, tau hyperphosphorylation begins in different regions of the brain in each tauopathy. In some regions, both neurons and glial cells develop tau hyperphosphorylation. Tau hyperphosphorylation is also observed in physiological conditions such as hibernation and brain development. In the first section of present article, we will review the spatiotemporal and cellular distribution of hyperphosphorylated tau in the most frequent tauopathies. In the second section, we will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau. Furthermore, we will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones. In the third section, we will speculate how the differences and similarities between hyperphosphorylated tau in physiological and pathological conditions could impact the elaboration of therapies to prevent tau pathology. In the fourth section, the different therapeutic approaches using tau as a direct or indirect therapeutic target will be presented.
... Transgenic C. elegans expressing in neurons the human fetal tau, formed by 352 amino acids and three microtubule-binding domains, were employed [116]. Although this strain, characterized by a defect in the synaptic transmission of cholinergic neurons, does not represent a model of tauopathy, it can be employed to investigate the role of tau hyperphosphorylation in toxicity [117]. Inhibition of DLD by 5-methoxyindole-2-carboxylic acid, as well as the suppression of the dld gene, increased worms' glucose levels, induced tau phosphorylation and reverted the neurotransmission defect. ...
The understanding of the genetic, biochemical, and structural determinants underlying tau aggregation is pivotal in the elucidation of the pathogenic process driving tauopathies and the design of effective therapies. Relevant information on the molecular basis of human neurodegeneration in vivo can be obtained using the nematode Caenorhabditis elegans (C. elegans). To this end, two main approaches can be applied: the overexpression of genes/proteins leading to neuronal dysfunction and death, and studies in which proteins prone to misfolding are exogenously administered to induce a neurotoxic phenotype. Thanks to the easy generation of transgenic strains expressing human disease genes, C. elegans allows the identification of genes and/or proteins specifically associated with pathology and the specific disruptions of cellular processes involved in disease. Several transgenic strains expressing human wild-type or mutated tau have been developed and offer significant information concerning whether transgene expression regulates protein production and aggregation in soluble or insoluble form, onset of the disease, and the degenerative process. C. elegans is able to specifically react to the toxic assemblies of tau, thus developing a neurodegenerative phenotype that, even when exogenously administered, opens up the use of this assay to investigate in vivo the relationship between the tau sequence, its folding, and its proteotoxicity. These approaches can be employed to screen drugs and small molecules that can interact with the biogenesis and dynamics of formation of tau aggregates and to analyze their interactions with other cellular proteins.
... In other neurodegenerative disorders, such as PSP (Flament et al., 1991), corticobasal degeneration (CBD; (Ksiezak-Reding et al., 1994), argyrophilic grain disease (AgD; (Simic, 2002)), and some cases of FTDP-17, sarkosyl extracts revealed that tau protein was separated as doublets of 64 and 69 kDa, which is a typical feature of class II tauopathies where isoforms with 4R predominates. On the other hand, the Pick's disease is characterized by the presence of pathological tau doublets of 60 and 64 kDa and contain mainly 3R tau isoforms (class III tauopathy) whereas in myotonic dystrophy type I (DM1) or Steinert's disease a major insoluble tau band of 60 kDa, and minor 64 and 69 kDa bands have been identified (Delacourte et al., 1996;Buee et al., 2000;Jovanov-Milosevic et al., 2012;Jadhav et al., 2015). Despite having all the characterization of Tau, the direct relevance of tau dysfunction and filament formation in these diseases has not been shown yet. ...
... The Ser202 specific tau phosphorylation differentiates the foetal tau from normal adult tau, and intriguingly, this corresponds to one of the abnormally phosphorylated sites during the early stages of AD . It has been demonstrated that hyperphosphorylation of foetal tau occurs in the distal portion of growing axons and when the majority of axonal terminals reach to their synaptic targets, hyperphosphorylation of foetal tau is minimalized (Jovanov-Milošević et al. 2012). It appears that differential level of foetal tau phosphorylation is tightly regulated and satisfies the requirements for dynamic and flexible microtubule system during development of nervous system. ...
Tauopathies represent a group of neurodegenerative disorder which are characterized by the presence of tau positive specialized argyrophilic and insoluble intraneuronal and glial fibrillar lesions known as neurofibrillary tangles (NFTs). Tau is a neuron specific microtubule binding protein which is required for the integrity and functioning of neuronal cells, and hyperphosphorylation of tau and its subsequent aggregation and paired helical filaments (PHFs) and NFTs has emerged as one of the major pathogenic mechanisms of tauopathies in human and mammalian model systems. Modeling of human tauopathies in Drosophila results in manifestation of associated phenotypes, and a recent study has demonstrated that similar to human and mammalian models, accumulation of insoluble tau aggregates in the form of typical neurotoxic NFTs triggers the pathogenesis of tauopathies in fly models. In view of the availability of remarkable genetic tools, Drosophila tau models could be extremely useful for in-depth analysis of the role of NFTs in neurodegeneration and tau aetiology, and also for the screening of novel gene(s) and molecule(s) which suppress the toxicity of tau aggregates.
... Intriguingly, tau alternative splicing shifts from short to long isoforms during normal brain development in all vertebrate species studied to date, including mouse, rat, guinea pig, human and even chicken [21,23]. Shorter isoforms have decreased microtubule binding affinity, suggesting that their expression in fetal life may allow greater neuronal plasticity [24]. ...
The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.
... Probably, in vivo chronic depletion and acute addition in cultured cells may regulate the tau kinase activities differently An interesting finding is the difference in phosphorylation between 3R and 4R tau in mouse brains. Some reports indicate the existence of isoform-dependent phosphorylation in vitro [47]. However, this is the first in vivo evidence showing their different, i.e. not identical, phosphorylation. ...
... The high phosphorylation of fetal tau is often discussed in relationship to the abnormal phosphorylation of tau in AD [3,15,18,47]. Many AD phosphorylation sites in tau are phosphorylated in fetal/perinatal brains. ...
Tau is a microtubule (MT)-associated protein that regulates MT dynamics in the axons of neurons. Tau binds to MTs via its C-terminal MT-binding repeats. There are two types of tau, those with 3 (3R) or 4 (4R) MT-binding repeats; 4R tau has a stronger MT-stabilizing activity than 3R tau. The MT-stabilizing activity of tau is regulated by phosphorylation. Interestingly, both the isoform and phosphorylation change at the time of neuronal circuit formation during postnatal development; highly phosphorylated 3R tau is replaced with 4R tau, which is less phosphorylated. However, it is not known how the transition of the isoforms and phosphorylation are regulated. Here, we addressed this question using developing mouse brains. Detailed analysis of developing brains revealed that the switch from 3R to 4R tau occurred during postnatal days 9 (P9) to P18 under the same time course as the conversion of phosphorylation from high to low. However, hypothyroidism, which is known to delay brain development, delayed the timing of tau dephosphorylation, but not the exchange of isoforms, indicating that isoform switching and phosphorylation are not necessarily linked. Furthermore, we confirmed this finding by using mouse brains that expressed a single isoform of human tau. Human tau, either 3R or 4R, reduced phosphorylation levels during development, even though the isoform did not change. We also found that 3R and 4R tau were phosphorylated differently in vivo even at the same developmental days. These results show for first time that the phosphorylation and isoform alteration of tau are regulated differently during mouse development.
... According to this "developmental hypothesis", some disorders with tau pathologies might reflect a recapitulation of a developmental phosphorylation programme [3,4,54,55]. Interestingly, the phosphorylation at Ser-202/Thr-205, a reliable marker of all tau pathologies in the adult brain, seems to play a pivotal role in normal brain development and is absent in DS brains. ...
Aims:
Down syndrome (DS) is a common cause of mental retardation accompanied by cognitive impairment. Comprehensive studies suggested a link between development and ageing, as nearly all individuals with DS develop Alzheimer disease (AD)-like pathology. However, there is still a paucity of data on tau in early DS to support this notion.
Methods:
Using morphometric immunohistochemistry we compared tau phosphorylation in normal brains and in brains of individuals with DS from early development until early postnatal life.
Results:
We observed in DS a critical loss of physiologic phosphorylation of tau. Rhombencephalic structures showed prominent differences between controls and DS using antibodies AT8 (Ser-202/Thr-205) and AT180 (Thr-231). In contrast, in the subiculum only a small portion of controls deviated from DS using antibodies AT100 (Thr-212/Ser-214) and AT270 (Thr-181). With exception of the subiculum, phosphorylation-independent tau did not differ between groups, as confirmed by immunostaining for the HT-7 antibody (epitope between 159 and 163 of the human tau) as well.
Discussion:
Our observations suggest functional tau disturbance in DS brains during development, rather then axonal loss. This supports the role of tau as a further important player in the pathophysiology of cognitive impairment in DS and related AD. This article is protected by copyright. All rights reserved.
