Alzheimer Disease (AD) is the most common type of dementia characterized clinically by progressive deterioration of cognitive functions including memory, reasoning, and language. The disease defining histopathological abnormalities include intracellular and extracellular deposits of Amyloid beta (Aβ) derived from the processing of the amyloid precursor protein (APP) (1). Besides Aβ, APP-derived C-terminal fragments (APP-CTFs) are now considered an early etiological hallmark of the disease triggering apathy, and synaptic plasticity and cognitive deficits (2). Mitochondrial dysfunction is one of the earliest features in the brains of AD patients. Pathological effects of Aβ and recently of APP-CTFs on mitochondrial function have been reported, including structure alterations, reduction in mitochondrial respiratory chain activity and increased reactive oxygen species (ROS) and mitophagy failure (3,4). Accumulating evidences highlight an instrumental and complex role of chronic innate neuroinflammation (mediated by microglia and astrocytes) and of adaptive immune responses (mediated by T cells) in AD pathophysiology. Moreover, the key role of mitochondria in regulating activation and functional differentiation of immune cells is an emerging feature. Our project hypothesizes that the aberrant and early accumulation of dysfunctional mitochondria in AD may promote and shape neuroinflammation, subsequently fostering disease progression.

The project aims to: i) Investigate innate and adaptive immune responses with a focus on the specific contribution of Aβ and APP-CTFs; ii) Study mitochondrial function in brain glial cells and in peripheral T cells; iii) Decipher the molecular mechanism underlying the interplay between mitochondria function and inflammation in AD; iv) Investigate the impact of mitochondrial function modulation on inflammation in AD.

The project will be developed using AD-like mice models and complementary biochemical, imaging, flux cytometry, mitochondrial functions analyses. Single cell RNA sequencing and proteomic analyses on isolated glial and T cells will be also applied.

The obtained results will demonstrate the intricate interplay between mitochondria dysfunction and inflammation in AD and identify key molecular pathway implicated in this process.

Keywords: Mitochondria, Alzheimer, Amyloid precursor protein, Inflammation.

I am looking for an organized, hard-working PhD-student holder of a Master2 degree in Molecular-Cellular/Biology or in Neurobiology/Neuroscience field. Interest in inflammation and animal experimentation would be a plus.

Interested candidates should send their curriculum vitae, Master’s grades, and the contact information for references to:

Dr.Chami Mounia

mchami@ipmc.cnrs.fr

Institut de Pharmacologie Moléculaire et Cellulaire

CNRS-UMR 7275

660 Route des Lucioles Sophia Antipolis

06560 VALBONNE

Tél : 0493953453

Selected publications

1. Lacampagne, A., Liu, X., Reiken, S., Bussiere, R.,…., Checler, F., Chami, M*., and Marks, A*. R. (2017) Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits. Acta Neuropathol 134, 749-767 (* last authors)
2. Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., …, Bauer, C., and Checler, F. (2016) Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathologica 132, 257-276
3. Vaillant-Beuchot, L., Mary, A., Pardossi-Piquard, R., Bourgeois, A., Lauritzen, I., Eysert, F., Kinoshita, P. F., …, Checler, F., and Chami, M. (2021) Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains. Acta Neuropathol 141, 39-65
4. Mary, A., Vaillant-Beuchot, L., Checler, F., and Chami, M. (2021) [Mitochondrial dysfunction and mitophagy failure in Alzheimer’s disease]. Med Sci (Paris) 37, 843-847

Contact: CHAMI MOUNIA

Address:

Array

Phone: +33 (0)493953453

Email

https://www.ipmc.cnrs.fr/cgi-bin/site.cgi