Tau Pathology In Alzheimer's Disease Research Articles

Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease.

The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from pre-synaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the pre-synaptic compartment in AD. Results demonstrate the abundance of tau, mainly C-terminal truncated tau, in synaptic terminals in aged control and in Alzheimer's disease (AD) samples. Tau fragments and dimers/oligomers are prominent in AD synapses. Following depolarization, tau release is potentiated in AD nerve terminals compared to aged controls. We hypothesize (i) endosomal release of the different tau peptides from AD synapses, and (ii) together with phosphorylation, fragmentation of synaptic tau exacerbates tau aggregation, synaptic dysfunction, and the spread of tau pathology in AD. Aβ = amyloid-beta.

Glycogen and amyloid-beta: key players in the shift from neuronal hyperactivity to hypoactivity observed in Alzheimer′s disease?

Glycogen and amyloid-beta: key players in the shift from neuronal hyperactivity to hypoactivity observed in Alzheimer′s disease?

Alzheimer's disease: Unique markers for diagnosis & new treatment modalities.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. In humans, AD becomes symptomatic only after brain changes occur over years or decades. Three contiguous phases of AD have been proposed: (i) the AD pathophysiologic process, (ii) mild cognitive impairment due to AD, and (iii) AD dementia. Intensive research continues around the world on unique diagnostic markers and interventions associated with each phase of AD. In this review, we summarize the available evidence and new therapeutic approaches that target both amyloid and tau pathology in AD and discuss the biomarkers and pharmaceutical interventions available and in development for each AD phase.

Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.

Cell cycle re-entry in Alzheimer's disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.

Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein Tau in Alzheimer's disease.

Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.

Synthesis and preliminary evaluation of 2‐arylhydroxyquinoline derivatives for tau imaging

Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of β-amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2-arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [(18) F]THK-523. THK-951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (Ki = 20.7 nM); thus, we radiosynthesized a (11) C-labeled THK-951 and further studied its potential as a tau PET probe. The [(11) C]THK-951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [(11) C]THK-951 for in vivo PET imaging of tau pathology in AD.

Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers. (18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-μM concentrations. (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

Distinct Functions of cis and trans Phosphorylated Tau in Alzheimer's Disease and their Therapeutic Implications

Proline-directed protein phosphorylation (pSer/Thr-Pro), a central signaling mechanism in diverse cellular processes in physiology and disease, has been proposed to be subject to further cis-trans conformational regulation by the unique prolyl isomerase Pin1. Until recently, no tool is available to directly detect the cis-trans conformation of Pin1-catalyzed cis-trans conformational changes in vivo. We have developed novel peptide chemistry that enables to generate the first antibodies that can distinguish cis from trans pThr231-Pro conformation in tau (p-tau). Using these conformation-specific antibodies, we have discovered that cis, but not trans, p-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in neurofibrillary degenerated neurons as Alzheimer's disease (AD) progresses, localizing to the dystrophic neurites, an early hallmark change that correlates with synaptic and cognitive deficits. Unlike trans p-tau, the cis not only cannot promote microtubule assembly, but also is more resistant to dephosphorylation and degradation, and prone to aggregation. Pin1 accelerates cis to trans conversion to prevent the accumulation of the pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. These findings develop the first tool to directly detect cis-trans prolyl isomerization, especially after phosphorylation and uncover cis p-tau as the very early pathogenic conformation leading to tau pathology and memory loss in AD. These results also suggest novel conformation-specific diagnoses and therapies for AD and likely others.

Knockout of 5‐lipoxygenase prevents dexamethasone‐induced tau pathology in 3xTg mice

Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer's disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5-lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid-mediated amyloid β (Ab) formation in vitro. In this article, we investigated the role of this pathway in modulating the development of the corticosteroid-dependent AD-like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for 1 week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO-/-) mice, and its effect on memory, amyloid-β and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Aβ levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF-13, which was specifically associated with an increase in the GSK3β activity. Additionally, dexamethasone-treated mice had a significant increase in the tau insoluble fraction and reduction in the postsynaptic protein PDS-95. By contrast, these modifications were blunted in the 3xTg/5LO-/- mice. Our findings highlight the functional role that 5LO plays in stress-induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor.

β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B

Protein phosphatase-2A (PP2A), an important phosphatase in dephosphorylating tau and preserving synapse, is significantly suppressed in Alzheimer's disease (AD), but the mechanism is not well understood. Here, we studied whether phosphotyrosyl phosphatase activator (PTPA) could activate PP2A by reducing its inhibitory phosphorylation at tyrosine 307 (P-PP2AC). We found that overexpression of PTPA activated PP2A by decreasing the level of P-PP2AC with reduced phosphorylation of tau, while knockdown of PTPA inhibited PP2A by increasing the level of P-PP2AC with enhanced tau phosphorylation. We also observed that expression of PTPA could upregulate the protein and mRNA levels of protein tyrosine phosphatase 1B (PTP1B) and simultaneous downregulation of PTP1B eliminated PTPA-induced PP2A activation. Importantly, we also found that the protein level of PTPA is downregulated in the brains of AD patients, and the AD transgenic mouse models with expression of mutant human amyloid precursor protein (hAPP) or the longest human tau (htau), respectively. Our data indicate that PTPA may activate PP2A through activating PTP1B and thus reducing the level of P-PP2AC, therefore upregulation of PTPA may represent a potential strategy in rescuing PP2A and arresting tau pathology in AD.

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.

Correlations between cortical and subcortical tau pathology

Recent studies indicate that tau pathology in Alzheimer's disease (AD) does not initially manifest in the cerebral cortex but in selected subcortical nuclei, in particular the locus ceruleus (LC). In this study we correlate both olfactory and brainstem tau pathology with neuritic Braak stages. We examined 239 unselected autopsy cases (57.3% female, 42.7% male; aged 55-102, mean 82.8 ± 9.7 SD years; AD, 44.8%; non-demented controls, 31.8%; Parkinson's disease, 5.0%; dementia with Lewy bodies, 2.5%; AD+Lewy body disease, 15.9%). Neuropathological examination according to standardized methods included immunohistochemistry and semiquantitative assessment of tau lesions in LC, substantia nigra (SN), dorsal motor nucleus of nervus vagus (dmX), and olfactory bulb (OB). In Braak stage 0, tau pathology (usually very sparse pretangle material) was seen in the OB in 52.9% and in the SN/LC in 44%. The prevalence of OB and subcortical tau pathology increased with increasing Braak stages and reached 100% in OB, SN and LC and 95.2% in dmX in Braak stage VI, respectively. The severity of tau pathology in OB and subcortical nuclei significantly (P < 0.001) correlated with Braak stages and these correlations remained statistically significant when controlling for concomitant α-synuclein pathology in the respective regions. Our finding of an increase in both prevalence and severity of OB, LC, SN and dmX tau pathology in AD with increasing Braak stages suggests that these regions become increasingly involved during AD progression rather than representing sites initially affected by AD-associated tau pathology.

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder

Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry. Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD. Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.

Tau Protein: Function and Pathology

Tau Protein: Function and Pathology

Spotlight on the July 26 Issue

#### Notable in Neurology This issue features an article that investigates the association of ultraearly hematoma growth with the CT angiography spot sign, hematoma expansion, and clinical outcomes in patients with acute intracerebral hemorrhage and another that investigates tau pathology in Alzheimer disease and mild cognitive impairment using PET. A featured article presents formal consensus-based guidance for the management of myasthenia gravis. ### Advanced interatrial block and ischemic stroke: The Atherosclerosis Risk in Communities Study The authors examine the association between advanced interatrial block and ischemic stroke in 14,716 participants followed for 22 years using a time-to-event analysis. Their findings suggest that advanced interatrial block, a marker of atrial fibrosis and abnormal cardiac remodeling of …

From tau biology to tauopathy: Toward new therapeutic strategies

Tau proteins belong to the family of microtubule-associated proteins. There are six Tau isoforms in the human brain. Tau isoforms regulate microtubule dynamics through their number of microtubule-binding domains (3 or4) and their state of phosphorylation: low levels of Tau phosphorylation allow for microtubule polymerization and stability; high levels of phosphorylation for microtubule depolymerization. Moreover, Tau proteins display an amino-terminal domain that is likely to bring them other specific biological functions including membrane interactions and DNA protection. Tau proteins aggregate in a number of neurodegenerative disorders referred to as Tauopathies, where they are always found hyperphosphorylated. However, inclusions found in Tauopathies are made of distinct sets of tau isoforms suggesting the existence of tau strains, similar to the prion strains. Another feature of Tauopathies reminiscent of prion-like disorders is that Tau aggregates can propagate amisfolded state to the inside of cells. Their microtubule-binding domains are likely to be crucial for the aggregation process since mutations in this area are found in fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, hyperphosphorylation may be an early toxic event before Tauproteins aggregate into filaments. To better understand the sequence of events leading to cell death and dementia, animal models have been developed. Nevertheless, most of these animal models are transgenic models over expressing tau with FTDP-17 mutations. One can ask if mutated tau really reflects this slow pathological process since mutations enhance aggregation rate of Tau proteins. Other models are thus needed. For proteomics analysis of Tau isoforms, human brains were obtained from the Lille NeuroBank and others. Animal models detailed in the present work are THY-Tau22 transgenic mice and a rat model obtained with stereotactic injections in the hippocampus of viral vectors encoding human tau (wild-type and mutated). In Alzheimer disease (AD), the Tau pathology is following cortico-cortical connections with a stereotyped, sequential and hierarchical pathway affecting large pyramidal neurons. Braak and Braak proposed a six stages spatiotemporal progression of Tau pathology in AD. Taupathology is also encountered in other neurodegenerative disorders. Our laboratory showed that depending on the neurological disorder considered, different sets of Tau protein isoforms were aggregated. For instance, the six Tau isoforms aggregate in AD whereas only three isoforms aggregate in Pick bodies of Pick's Disease. These observations suppose that subsets of Tau isoforms are expressed in sub neuronal populations, or alternatively, a defective splicing of Tau is an early event of neurodegeneration. Propagation of Tau pathology may also be specific to these different Tauisoforms. The use of animal models will be a key asset for understanding Taupathology. Using the Thy-Tau22 mouse transgenic line developed in our laboratory, analysis of the kinetics of Tauphosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a dys-connection between cognition deficits and neuronal cell death. This model exhibits progressive neuron-specific AD-like Tau pathology devoid of any motor deficits. A progressive development of Taupathology is observed in the hippocampus and amygdala, which parallels behavioural impairments as well as electrophysiological alterations. These latter changes are observed despite of any striking loss of neuronal/synaptic markers until 12 months of age in the hippocampus. In addition, in the hippocampus, hyper- and abnormally phosphorylated Tau species accumulate within the somato-dendriticarea, supporting a possible influence on hippocampal-dependent plasticity always confirmed by behavioural and electrophysiological evaluations. In conclusion, AD and other Tauopathies have likely different etioliges. They are characterized by differenct Tau aggregates, which may spread in different ways and explain their different clinical presentations. Animal models of Tau pathology may mimie part of the pathology (phosphorylation and/or aggregation, propagation vs. diffusion) and help for the development of new, innovative therapeutic strategies.

β-Carboline Compounds, Including Harmine, Inhibit DYRK1A and Tau Phosphorylation at Multiple Alzheimer's Disease-Related Sites

Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.

Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer's disease and progressive supranuclear palsy

Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer's disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD.