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ALZHEIMER'S DISEASE

Basic Research

Cellular models

In-vitro co-culture systems (primary cell cultures)

Rat/mouse primary cell cultures of neurons/astrocytes/ or mixed cultures exposed to various mutated proteins implicated in the pathology and delivered either as recombinant proteins or following overexpression through viral vector infection.

Analyzing Tools

- Videomicroscopy
- Flux cytometrye
- Biochemistry
- Functional analyses using radioactivity.



























Preclinical Research

Murins models of amyloïdogenesis

Transgenic mouse models to study amyloidogenesis and screen in vivo potential therapeutic agents

- Models adapted to the search of therapeutics specifically targeting amyloidosis (synthesis inhibitors, anti-aggregate molecules, anti-amyloid immunotherapies …)

- Models adapted to the search of amyloid plaque imaging markers.

Analyzing tools : Detection and quantification of lesions and assessment of therapeutic efficacy

- amyloid load detection in plasma

- 3D reconstruction of whole brain histological sections for group studies : this approach allows quantitative 3D evaluation of several bio-markers of interest such as glucose consumption (2DG autoradiography), morphometric analyzes of the whole brain and amyloid load using used independent supervised (brain atlases) or non-supervised (Statistical Parametric Mapping) analyzes.

- Main targeted applications relate to the characterization of experimental animal models as well as the proof of efficacy of new therapeutic interventions.

- In addition, the whole brain 3D-reconstruction of histological sections offers the unique opportunity to study potential correlations between in vivo imaging and post-mortem data (e.g. validation of imaging biomarkers, imaging protocols, instrumental devices, etc…).

- Preclinical PET imaging

* Cerebral metabolic rate of glucose : 18F-FDG

- Correlative studies between PET data and 3D whole brain histological sections

- High field MR imaging (11.7T)

* MRI follow-up of amyloïd load in-vivo
* T2-weighted imaging
* DTI
* Proton MR spectroscopy, LC Model quantification
* Glutamate CEST-imaging
* Diffusion MR spectroscopy of various brain metabolites of interest (NAA, Glu, Gln, etc…)
* MRI morphometric imaging with manual/automatic delineation and quantification of cerebral volumes/structures
* Hippocampal sub-fields imaging/quantification through high-resolution MR microscopy

Rat models of Tauopathies

Models induced through intra-hippocampal overexpression of wild-type/mutated (P301L) forms of the tau protein

- Lentiviral vector mediated overexpression of various constructs over-expressing different species of the tau protein (wild-type, P301L, wild-type fused to a pro-aggregating peptide) allowing the study of aggregation at different stages of the process. The model is associated with a spreading of the tauopathy (propagation of the pathology in the brain following local surexpression of the construct) making this model particularly adapted to the search of innovative therapies targeting the aggregation process.

- AAV vectors mediated overexpression of various constructs over-expressing different species of the tau protein (wild-type, P301L, wild-type fused to a pro-aggregating peptide) allowing the study of aggregation at different stages of the process. Compared to the previous one, this model is associated with a more widespread pathology making this model particularly adapted to PET imaging of tau-specific biomarkers.

Analyzing tools in rodent models : Detection and quantification of lesions and assessment of therapeutic efficacy

- Design, construction and production of lentiviral and AAV vectors allowing the in vivo modelling of neuropathological processes

- Histological analyses, immunohistochemistry, in situ hybridization (floating sections, paraffine section, Ventana BenchMark automatic staining system)

- 3D reconstruction of whole brain histological volumes ; automated analysis of the 3D histological volumes reconstructed and in vivo/post-mortem co-registration

- Assessment of emotional and cognitive behavior (open field maze, Morris maze, Y maze, fear conditionning, elevated maze

- Preclinical PET imaging

*Tau specific biomarkers : 18F-THK523, 18F-T808, 18F-T807 and/or new ligands

*Neuroinflammation PET tracer : 18F-DPA714

*Metabolic rate of glucose and/or mitochondrial complex I activity: 18F-FDG/18F-BCPP

* Amyloid marker : 18F-AV45,11C-PIB

* Cerebral metabolic rate of glucose : 18F-FDG

- Correlative studies between PET data and 3D whole brain histological sections

- High field MR imaging (11.7T)

* MRI follow-up of amyloïd load in-vivo
* T2-weighted imaging
* DTI
* Proton MR spectroscopy, LC Model quantification
* Glutamate CEST-imaging
* Diffusion MR spectroscopy of various brain metabolites of interest (NAA, Glu, Gln, etc…)
* MRI morphometric imaging with manual/automatic delineation and quantification of cerebral volumes/structures
* Hippocampal sub-fields imaging/quantification through high-resolution MR microscopy

Small (Microcebus murinus) non-human primate models

Models of cerebral aging associated to cognitive deficits and cerebral atrophy

- Animal model displaying a normal expression of the APP or the Tau proteins, similar to the one present in the human. This species has the potential to develop spontaneously an amyloidogenesis and neurofibrillary tangles.

- This animal model is suitable for studies aiming at targeting disease modifying strategies such as dietary intervention/modulation or neurotrophic factors as well as for the evaluation of the potential side effects of new anti-amyloid strategies.

- The model is also adapted to the search of aggravating factors of cerebral aging (e.g. the prion hypothesis of Alzheimer disease, brain toxics, etc…).

Analyzing tools : Detection and quantification of lesions and assessment of therapeutic efficacy

- amyloid load detection in plasma

- 3D reconstruction of the whole primate brain histological sections for group studies: this approach allows quantitative 3D evaluation of several bio-markers of interest such as glucose consumption (2DG autoradiography), morphometric analyzes of the whole brain and amyloid load using used independent supervised (brain atlases) or non supervised (Statistical Parametric Mapping) analyzes.

- Main targeted applications relate to the characterisation of experimental animal models as well as the proof of efficacy of new therapeutic interventions.

- In addition, the whole brain 3D-reconstruction of histological sections offers the unique opportunity to study potential correlations between in vivo imaging and post-mortem data (e.g. validation of imaging biomarkers, imaging protocols, instrumental devices, etc…).

- Assessment of emotional and cognitive behavior (open field maze, Morris maze, Y maze, fear conditionning, elevated maze

- Preclinical PET imaging

* Cerebral metabolic rate of glucose : 18F-FDG

- Correlative studies between PET data and 3D whole primate brain histological sections

- High field MR imaging (11.7T)

* MRI follow-up of amyloïd load in-vivo
* T2-weighted imaging
* DTI
* Proton MR spectroscopy, LC Model quantification
* Glutamate CEST-imaging
* Diffusion MR spectroscopy of various brain metabolites of interest (NAA, Glu, Gln, etc…)
* MRI morphometric imaging with manual/automatic measures of cerebral volumes/structures
* Hippocampal sub-fields imaging/quantification by high-resolution MR microscopy

Large Non-human Primate models in Macaques

Models induced through intra-hippocampal overexpression of wild-type/mutated (P301L) forms of the tau protein

- Lentiviral vector mediated overexpression of various constructs over-expressing different species of the tau protein (wild-type, P301L, wild-type fused to a pro-aggregating peptide) allowing the study of aggregation at different stages of the process. The model is associated with a spreading of the tauopathy (propagation of the pathology in the brain following local surexpression of the construct) making this model particularly adapted to the search of innovative therapies targeting the aggregation process.

- AAV vectors mediated overexpression of various constructs over-expressing different species of the tau protein (wild-type, P301L, wild-type fused to a pro-aggregating peptide) allowing the study of aggregation at different stages of the process. Compared to the previous one, this model is associated with a more wide spread pathology making this model particularly adapted to PET imaging of tau-specific biomarkers.

Analyzing tools : Detection and quantification of lesions and assessment of therapeutic efficacy

- Design, construction and production of lentiviral and AAV vectors allowing the in vivo modelling of neuropathological processes

- Histological analyses, immunohistochemistry, in situ hybridization (floating sections, paraffine section, Ventana BenchMark automatic staining system)

- 3D reconstruction of whole brain histological volumes ; automated analysis of the 3D histological volumes reconstructed and in vivo/post-mortem co-registration

- Quantitative analyses of cognitive behavior

* CANTAB test Battery for monkey
* In-house test battery running on tactile screens (can be adapted on purpose)

- Preclinical PET imaging

* Cerebral metabolic rate of glucose : 18F-FDG
* Tau specific biomarkers : 18F-THK523, 18F-T808, 18F-T807
* Neuroinflammation PET tracer: 18F-DPA714
* Amyloid marker : 18F-AV45,11C-PIB

- High field MR imaging (7T)

* T2-weighted imaging
* Proton MR spectroscopy, LC Model quantification
* Diffusion MR spectroscopy of various brain metabolites of interest (NAA, Glu, Gln, etc…)
* MRI morphometric imaging with manual/automatic delineation and quantification of cerebral volumes/structures

Clinical research

Phase I clinical trials on healthy volunteers and phase II clinical trials on cohorts of affected patients

Clinical investigation Center of the Pitié-Sapétrière Hospital (IHU Neuroscience Translationnelle)

- Tissue analyses and Genetic characterization

- Cohorte Insight

Imaging tools

PET imaging

- Available at the site of Pitié-Salpétrière

* amyloid marker : 18F-AV45
* Cerebral metabolic rate of glucose : 18F-FDG

- Available at the Service Hospitalier Frédéric Joliot

* amyloid markers : 11C-PiB or commercial fluorinated (18F) derivatives such as 18F-AV45 (Amyvid™), 18F-Flutemetamol (Vizamyl™), 18F-Florbetaben (Neuraceq™)…,
* tau PET Tracer : 18F-AV1451
* neuro-inflammation PET tracer : 18F-DPA7144
* Marker of neuronal insult : 11C-Flumazenil
* C e : 18F-FDG

- Available at the Henri Mondor hospital

* amyloid markers : 18F-AV45 (Amyvid™)
* Cerebral metabolic rate of glucose : 18F-FDG

SPECT imaging

- DaTSCAN, as a means to differentiate Lewy body dementia (positive at DaTSCAN) from Alzheimer (negative at DaTSCAN)

MR imaging (all sequences validated by the CATI)

- Available at the Pitié-Salpétrière site

* T2-weighted imaging at 3T
* DTI
* morphometric analyses
* perfusion imaging

- Available at Henri Mondor hospital

* T2-weighted imaging at 3T
* DTI
* morphometric analyses
* perfusion imaging