Ilie-Cosmin Stancu

Models of β-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism

The amyloid cascade hypothesis has been the prevailing hypothesis in Alzheimer’s Disease research, although the final and most wanted proof i.e. fully successful anti-amyloid clinical trials in patients, is still lacking. This may require a better in depth understanding of the cascade. Particularly, the exact toxic forms of Aβ and Tau, the molecular link between them and their respective contributions to the disease process need to be identified in detail. Although the lack of final proof has raised substantial criticism on the hypothesis per se, accumulating experimental evidence in in vitro models, in vivo models and from biomarkers analysis in patients supports the amyloid cascade and particularly Aβ-induced Tau-pathology, which is the focus of this review. We here discuss available models that recapitulate Aβ-induced Tau-pathology and review some potential underlying mechanisms. The availability and diversity of these models that mimic the amyloid cascade partially or more complete, provide tools to study remaining questions, which are crucial for development of therapeutic strategies for Alzheimer’s Disease.

Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.

Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimers disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimers disease and related tauopathies.

Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo.

Genetic, clinical, histopathological and biomarker data strongly support Beta-amyloid (Aβ) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer‘s Disease (AD), while the underlying mechanism remains unclear. In vivo preclinical models have reproducibly recapitulated Aβ-induced Tau-pathology. Tau pathology was thereby also induced by aggregated Aβ, in functionally connected brain areas, reminiscent of a prion-like seeding process. In this work we demonstrate, that pre-aggregated Aβ can directly induce Tau fibrillization by cross-seeding, in a cell-free assay, comparable to that demonstrated before for alpha-synuclein and Tau. We furthermore demonstrate, in a well-characterized cellular Tau-aggregation assay that Aβ-seeds cross-seeded Tau-pathology and strongly catalyzed pre-existing Tau-aggregation, reminiscent of the pathogenetic process in AD. Finally, we demonstrate that heterotypic seeded Tau by pre-aggregated Aβ provides efficient seeds for induction and propagation of Tau-pathology in vivo. Prion-like, heterotypic seeding of Tau fibrillization by Aβ, providing potent seeds for propagating Tau pathology in vivo, as demonstrated here, provides a compelling molecular mechanism for Aβ-induced propagation of Tau-pathology, beyond regions with pre-existing Tau-pathology (entorhinal cortex/locus coeruleus). Cross-seeding along functional connections could thereby resolve the initial spatial dissociation between amyloid- and Tau-pathology, and preferential propagation of Tau-pathology in regions with pre-existing ‘silent’ Tau-pathology, by conversion of a ‘silent’ Tau pathology to a ‘spreading’ Tau-pathology, observed in AD.

Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease

Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimers disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid‐β (Aβ) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early‐onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F+/T+ mice, and phenotypically compared them to their respective parental strains, denoted F+/T– and F–/T+ respectively, as controls. We found dramatically aggravated tauopathy (~10‐fold) in F+/T+ mice compared to the parental F–/T+ mice. In contrast, amyloidosis was unaltered compared to the parental F+/T– mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F+/T+ displayed aggravated cognitive deficits in a hippocampus‐dependent spatial navigation task, compared to the parental F+/T– strain, while parental F–/T+ mice did not display cognitive impairment. Basal synaptic transmission was impaired in F+/T+ mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F+/T+ mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aβ species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aβ species as initiator and pathological Tau species as executor.—Stancu, I.‐C., Ris, L., Vasconcelos, B., Marinangeli, C., Goeminne, L., Laporte, V., Haylani, L. E., Couturier, J., Schakman, O., Gailly, P., Pierrot, N., Kienlen‐Campard, P., Octave, J.‐N., Dewachter, I. Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimers disease. FASEB J. 28, 2620–2631 (2014). www.fasebj.org

Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau

Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimers disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimers disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau.

Preclinical models of Alzheimer’s disease for identification and preclinical validation of therapeutic targets: from fine-tuning strategies for validated targets to new venues for therapy

Animal models recapitulate characteristic pathological features of Alzheimer’s disease and related tauopathies, in addition to several phenotypic traits reminiscent of the disease. These animal models have been used as a central tool in the identification of therapeutic targets and their preclinical validation. A major focus has been on therapies targeting amyloid-β (Aβ). However, clinical trials aiming at Aβ have led to the general view that once the disease process has started, multitargeted combined therapies are required for disease-modifying therapies, including downstream targets in the amyloid cascade. These include not only tau as a crucial executor of the pathogenesis, but also mechanisms involved in spreading of tau-pathology and in Aβ-induced tau-pathology. In this work, we review the use of preclinical models for identification of targets for disease-modifying therapies. We thereby focus on the initial validation of targets currently tested in clinical trials, their constraints and subsequent fine-tuning, and on new venues for future therapies currently under study in preclinical models.