Secondary Tauopathies Research Articles

Secondary tauopathy in a genetic synucleinopathy, mitochondrial protein–associated neurodegeneration (MPAN)

AbstractBackgroundTauopathy and α‐synucleinopathy often occur together in human brain diseases but most commonly in the context of β‐amyloidosis. Tauopathy induced by α‐synucleinopathy in the absence of β‐amyloid has been demonstrated in vitro and in cultured cells but compelling examples of this in human disease rarely occur, most commonly in familial Parkinson's disease due to mutations in the α‐synuclein gene. Mitochondrial protein‐associated neurodegeneration (MPAN) due to mutations in C19orf12 produces neurodegeneration with brain iron accumulation as well as widespread α‐synucleinopathy. We report here on the findings and significance of associated tauopathy in MPAN.MethodFour patients with genetically confirmed MPAN were referred for brain autopsy and a complete histologic and immunohistochemical evaluation was undertaken for lesions and proteinopathies of common neurodegenerative diseases as well as the specific reported lesions of MPAN.ResultAll patients had hallmark pathologic features of MPAN including atrophy, gliosis, and iron accumulation involving the globus pallidus as well as abundant α‐synucleinopathy manifest as Lewy bodies and neurites thoughout the brain. Tauopathy was present in each case with neurofibrillary tangles distributed in Braak stages I to V with pretangles and more widely distributed tau‐positive dystrophic neurites. The distribution and regional burden of tauopathy was less than that of α‐synucleinopathy in each case. β‐amyloid or TDP‐43 abnormalities were not identified in any case.ConclusionThe lesional burden and distribution in MPAN are consistent with a pathogenetic model in which dysmetabolism of α‐synuclein is sufficient, in the absence of other common neurodegenerative pathologies, to induce tauopathy. Study of rare familial diseases such as MPAN may enhance our understanding of the pathogenesis of more common idiopathic neurodegenerative diseases.

Tauopathy and Movement Disorders-Unveiling the Chameleons and Mimics.

The spectrum of tauopathy encompasses heterogenous group of neurodegenerative disorders characterized by neural or glial deposition of pathological protein tau. Clinically they can present as cognitive syndromes, movement disorders, motor neuron disease, or mixed. The heterogeneity in clinical presentation, genetic background, and underlying pathology make it difficult to classify and clinically approach tauopathy. In the literature, tauopathies are thus mostly highlighted from pathological perspective. From clinical standpoint, cognitive syndromes are often been focussed while reviewing tauopathies. However, the spectrum of tauopathy has also evolved significantly in the domain of movement disorders and has transgressed beyond the domain of primary tauopathies. Secondary tauopathies from neuroinflammation or autoimmune insults and some other “novel” tauopathies are increasingly being reported in the current literature, while some of them are geographically isolated. Because of the overlapping clinical phenotypes, it often becomes difficult for the clinician to diagnose them clinically and have to wait for the pathological confirmation by autopsy. However, each of these tauopathies has some clinical and radiological signatures those can help in clinical diagnosis and targeted genetic testing. In this review, we have exposed the heterogeneity of tauopathy from a movement disorder perspective and have provided a clinical approach to diagnose them ante mortem before confirmatory autopsy. Additionally, phenotypic variability of these disorders (chameleons) and the look-alikes (mimics) have been discussed with potential clinical pointers for each of them. The review provides a framework within which new and as yet undiscovered entities can be classified in the future.

Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

Since the early reports of neurofibrillary Tau pathology in brains of some Huntington’s disease (HD) patients, mounting evidence of multiple alterations of Tau in HD brain tissue has emerged in recent years. Such Tau alterations range from increased total levels, imbalance of isoforms generated by alternative splicing (increased 4R-/3R-Tau ratio) or by post-translational modifications such as hyperphosphorylation or truncation. Besides, the detection in HD brains of a new Tau histopathological hallmark known as Tau nuclear rods (TNRs) or Tau-positive nuclear indentations (TNIs) led to propose HD as a secondary Tauopathy. After their discovery in HD brains, TNIs have also been reported in hippocampal neurons of early Braak stage AD cases and in frontal and temporal cortical neurons of FTD-MAPT cases due to the intronic IVS10+16 mutation in the Tau gene (MAPT) which results in an increased 4R-/3R-Tau ratio similar to that observed in HD. TNIs are likely pathogenic for contributing to the disturbed nucleocytoplasmic transport observed in HD. A key question is whether correction of any of the mentioned Tau alterations might have positive therapeutic implications for HD. The beneficial effect of decreasing Tau expression in HD mouse models clearly implicates Tau in HD pathogenesis. Such beneficial effect might be exerted by diminishing the excess total levels of Tau or specifically by diminishing the excess 4R-Tau, as well as any of their downstream effects. In any case, since gene silencing drugs are under development to attenuate both Huntingtin (HTT) expression for HD and MAPT expression for FTD-MAPT, it is conceivable that the combined therapy in HD patients might be more effective than HTT silencing alone.

Progressive age-dependent motor impairment in human tau P301S overexpressing mice

This study assessed the development of motor deficits in female hTau.P301S transgenic mice from 1.5 to 5.5 months of age. The test battery included clasping reflex, grid hanging, Rotarod test, spontaneous explorative activity, Catwalk gait analysis, and nest building. Starting from the age of 2–3 months the mice showed marked hyperactivity, abnormal placing of weight on the hindlimbs and defective nest building in their home cage. These behavioral impairments did not progress with age. In addition, there was a progressive development of hindlimb clasping, inability to stay on a rotating rod or hang on a metal grid, and gait impairment. Depending on the measured output parameter, the motor impairment became significant from 3 to 4 months onwards and rapidly worsened until the age of 5.5 months with little inter-individual variation. The progressive motor impairment was paralleled by a robust increase in AT8 p-tau positive neurons in deep cerebellar nuclei and pontine brainstem between 3 and 5.5 months of age. The quick and steadily progressive motor impairment between 3 and 5.5 months of age accompanied by robust development of tau pathology in the hindbrain makes this mouse well suited for preclinical studies aiming at slowing down tau pathology associated with primary or secondary tauopathies.

Tau Interacting Proteins: Gaining Insight into the Roles of Tau in Health and Disease.

Tau is most intensely studied in relation to its executive role in Tauopathies, a family of neurodegenerative disorders characterized by the accumulation of Tau aggregates [15, 21, 38, 75, 89, 111, 121, 135, 175, 176, 192]. Tau aggregation in the different Tauopathies differs in the affected cell type, the structure of aggregates and Tau isoform composition. However, in all Tauopathies, accumulation of pathological Tau in well-characterized and well-defined brain regions, correlates strongly with symptoms associated with the dysfunction of this brain region. Hence, symptoms of neurodegenerative Tauopathies can range from motoric to cognitive and behavioral symptoms, even extending to deterioration of vital functions when the disease progresses, or combinations of different symptoms governed by the affected brain regions. The most common Tauopathies are corticobasal degeneration (CBD), Pick's disease, progressive supranuclear palsy (PSP) and frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17). However a growing number of diseases are characterized by Tau aggregation amounting to a large family of more than 20 disorders [176]. Most Tauopathies are sporadic, and are hence linked to a combination of environmental and genetic risk factors. However, mutations in MAPT have been identified which are autosomal dominantly linked to Tauopathies, including FTDP, PSP and CBD [94, 163, 185] (Alzforum, https://www.alzforum.org/mutations/mapt ). More than 80 mutations have been identified in MAPT, both in intronic and exonic regions of the human MAPT. These mutations can be classified as missense mutations or splicing mutations. Most missense mutations cluster in or near the microtubule binding site of Tau, while most splicing mutations affect the splicing of exon 10 (encoding the R2 domain), and hence affect the 3R/4R ratio. While Alzheimer's disease (AD), is the most prevalent Tauopathy, no mutations in MAPT associated with AD have been identified. Brains of AD patients are pathologically characterized by the combined presence of amyloid plaques and neurofibrillary tangles [171]. Familial forms of AD, termed early onset familial AD (EOFAD) with clinical mutations in APP or PS1/2, have an early onset, and are invariably characterized by the combined presence of amyloid and Tau pathology [24, 80, 170]. These EOFAD cases, identify a causal link between APP/PS1 misprocessing and the development of Tau pathology and neurodegeneration [80, 170]. Furthermore, combined genetic, pathological, biomarker and in vivo modelling data, indicate that amyloid pathology precedes Tau pathology, and support a role for Aβ as initiator and Tau as executor in the pathogenetic process of AD [80, 96, 97]. Hence, AD is often considered as a secondary Tauopathy (similar as for Down syndrome patients), in contrast to the primary Tauopathies described above. Tau aggregates in Tauopathies vary with respect to the ratio of different Tau isoforms (3R/4R), to the cell types displaying Tau aggregation and the structure of the aggregates. However, in all Tauopathies a strong correlation between progressive development of pathological Tau accumulation and the loss of the respective brain functions is observed.

Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions.

Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model.Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments.Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes.Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.

Molecular Pathogenesis of the Tauopathies

The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences in Tau pathology that are characteristic of the spectrum of frontotemporal lobar degeneration as primary tauopathies and of Alzheimer's disease as a secondary tauopathy, as well as the commonalities and differences between the familial and sporadic forms. Furthermore, we discuss selected advances in transgenic animal models in delineating the different pathomechanisms of Tau.

Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias

Imaging of pathological tau with positron emission tomography (PET) has the potential to allow early diagnosis of the dementias and monitoring of disease progression, including assessment of therapeutic interventions, in vivo. The first generation of tau PET tracers, including the carbazole flortaucipir and the 2-arylquinolines of the THK series, are now used in clinical research; however, concerns have been raised about off-target binding and low sensitivity.With the aim to determine the nature of tau pathology depicted by structurally distinct tau ligands we carried out a microscopic neuropathological evaluation in post-mortem human brain tissue of cases with primary and secondary tauopathies. Carbazole and 2-arylquinoline binding was only observed in cases with Alzheimer’s disease and one case with frontotemporal dementia and parkinsonism linked to chromosome 17 exhibiting a R406W MAPT mutation. In end stage Alzheimer’s disease cases, fluorescent imaging with the carbazole T726 and the 2-arylquinoline THK-5117 revealed high inter- and intra-case variability of tracer binding, and this was corroborated by quantitative phosphorimaging with the PET tracer [18F]THK-5117. Microscopic analysis of the pathological inclusions revealed that the fluorescent tracers preferentially bind to premature tau aggregates. Whilst T726 binding was limited to neuronal tau, THK-5117 additionally depicted neuritic tau. Neither tracer depicted tau in pre-symptomatic disease.Our results highlight limitations of the first generation of tau PET tracers, in particular lack of correlation between pathological tau load and tracer binding, limited sensitivity to tau in early disease, and high variability in tracer binding between and within cases. Concerns remain that these limitations may also affect the next generation tracers as they target the same high affinity binding site. Therefore, it is crucial to assess inter- and intra-subject correlation of tracer binding with pathological tau load in post-mortem tissue studies, and to rigorously assess novel tau PET tracers before translation into clinical studies.

Tau Spreading Mechanisms; Implications for Dysfunctional Tauopathies.

Tauopathies comprise a group of progressive age-associated neurodegenerative diseases where tau protein deposits are found as the predominant pathological signature (primary tauopathies) or in combination with the presence of other toxic aggregates (secondary tauopathies). In recent years, emerging evidence suggests that abnormal tau accumulation is mediated through spreading of seeds of the protein from cell to cell, favouring the hypothesis of a prion-like transmission of tau to explain the propagation of the pathology. This would also support the concept that the pathology initiates in a very small part of the brain before becoming symptomatic and spreads across the brain over time. To date, many key questions still remain unclear, such as the nature of the tau species involved in the spreading, the precise seeding/template and uptaking mechanisms or the selectivity explaining why certain neurons are affected and some others are not. A better understanding of the tau spreading machinery will contribute to the development of new therapeutic approaches focused on halting the abnormal propagation, offering also new perspectives for early diagnosis and preventive therapies. In this review, we will cover the most recent advances in tau spreading mechanisms as well as the implications of these findings for dysfunctional tauopathies.

Update on tauopathies.

The purpose of this review is to provide an update on the role of tau beyond the stabilization of microtubules and on the clinical, pathological, diagnostic and therapeutic aspects of tauopathies. Beyond its function as a microtubule-associated tau protein, tau is also involved in gene regulation, signal transduction and metabolism. Experimental models allow for the development of new diagnostic and therapeutic tools. Tauopathies encompass different disorders that may manifest with various clinical syndromes. Differential diagnosis with other proteinopathies is still challenging. Cerebrospinal fluid biomarkers and radiotracers were extensively studied in the last year. Although diagnostic accuracy remains deceiving in non-Alzheimer's disease tauopathies, positron emission tomography tau tracers could be used to monitor disease progression. Despite the advent of novel therapeutic approaches and the increasing number of clinical trials in tauopathies, accurate clinical diagnosis is still an unmet need and better tau biomarkers are still desperately needed. Although primary taupathies are rare and heterogeneous disorders, their combined prevalence and the importance of tau disorder in Alzheimer's disease and secondary tauopathies makes research on tauopathy a priority - because it could benefit many patients.

GENETIC MUTATIONS IN MAPT AND SIGNIFICANT VARIABILITY IN TAU PROTEIN MODIFICATIONS INDICATE THE EXISTANCE OF A WIDE ARRAY OF STRAINS WITHIN AND ACROSS PRIMARY AND SECONDARY TAUOPATHIES

Tau proteins aggregate into morpholigically distinct lesions in primary and secondary tauopathies. These signature lesions result from deposition of tau proteins that are uniquely modified via missense mutation and/or post-translational modification for each disease strain. Identifying the unique tau protein abnormalities that lead to specific neurodegenerative diseases would be useful in their early diagnosis and treatment. Biochemical and immunohistochemical analyses of tau aggregates and lesions in AD, PSP, CBD, GGT, and FTDP-17 can be used to demonstrate that the tau protein modifications observed in each disease result from tau that is uniquely modified and thereby forms the basis of the distinct morphological aggregates and disease strains observed. Here data collected using the sarkosyl-insoluble tau fractions from tisssue samples of pathologically diagnosed patients with either sporadic or familial primary tauopathies allows for the direct observation of the modifications that lead to accumulation in each disease and the resulting structural implications. Most interesting is the variability of the tau proteins that actually collect within like diseases opening up the possibility that tau strains may exist within any given tauopathy even as the clinical manesfestation appears similar. This indicates that early and specific identification and detection of these strains is crititcal for the development of therapies for these diseases. Strutural analyses of tau filaments from each primary and secondary tauopathy using electron microscopy and IHC amyloid staining methods suggest that the tau protein modifications have a limited affect on the tau filament morphology or tau protein isoforms incorporated into the aggregates even as the truncation and phosphorylation events can vary widely as observed by western blotting of these samples. Tau strains need to be identified and validated using traditional methods to confirm they can be developed for diagnostic and therapeutic purposes.

Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A\u03b242 levels

The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82–96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-β (Aβ) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and Aβ42 as markers of brain tauopathy and β-amyloidosis.

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies.

Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies.

Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease.

The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

Exploiting the Diversity of the Heat-Shock Protein Family for Primary and Secondary Tauopathy Therapeutics

The heat shock protein (Hsp) family is an evolutionarily conserved system that is charged with preventing unfolded or misfolded proteins in the cell from aggregating. In Alzheimer’s disease, extracellular accumulation of the amyloid β peptide (Aβ) and intracellular aggregation of the microtubule associated protein tau may result from mechanisms involving chaperone proteins like the Hsps. Due to the ability of Hsps to regulate aberrantly accumulating proteins like Aβ and tau, therapeutic strategies are emerging that target this family of chaperones to modulate their pathobiology. This article focuses on the use of Hsp-based therapeutics for treating primary and secondary tauopathies like Alzheimer’s disease. It will particularly focus on the pharmacological targeting of the Hsp70/90 system and the value of manipulating Hsp27 for treating Alzheimer’s disease.

PATU2 Novel truncation mutation of PRNP causes chronic diarrhoea, sensory neuropathy and autonomic failure associated with prion protein deposition in the cerebral blood vessels and small bowel

The inherited prion diseases (IPD) are a group of dominantly inherited neurodegenerative disorders caused by mutation of the prion protein gene (PRNP). Although clinically heterogeneous, IPDs are generally associated with...

A NH2 Tau Fragment Targets Neuronal Mitochondria at AD Synapses: Possible Implications for Neurodegeneration

Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-beta (Abeta)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20-22 kDa NH2-truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2-truncated tau form is also found in other human, not AD-tauopathies, while its presence in AD patients is linked to Abeta multimeric species and likely to pathology severity. Finally native, patient-derived, Abeta oligomers-enriched extracts likely impair the mitochondrial function by the in vitro production of 20-22 kDa NH2-tau fragments in mature human SY5Y and in rat hippocampal neurons. Thus our findings suggest that the mitochondrial NH2-derived tau peptide distribution may exacerbate the synapse degeneration occurring in tauopathies, including AD, and sustain the in vivo NH-2 tau cleavage inhibitors as an alternative drug discovery strategies for AD therapy.

Upper Airway Dysfunction of Tau-P301L Mice Correlates with Tauopathy in Midbrain and Ponto-Medullary Brainstem Nuclei

Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive tauopathy in identified neural circuits. Because patients with tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.

AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice.

In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.