Job ID: 106518

PhD project –Mechanisms of action of MT5-MMP in Alzheimer’s disease and therapeutic modulation using viral-mediated transgenic strategies

Position: Ph.D. Student

Deadline: 2 April 2023

Employment Start Date: 2 October 2023

Contract Length: 3 years

City: Marseille

Country: France

Institution: Aix Marseille Université

Department: Institute of Neuropathophysiology (INP)

Description:

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD scholarships for students with a master’s degree in a non-French university.

The following project is one of the 14 proposed projects. Not all proposed projects will be funded, check our website for details.

RESEARCH PROJECT :

  • State of the art

We found that the proteinase MT5-MMP (MT5 thereafter) promotes amyloidosis and neuroinflammation, while MT5 KO prevents the latter as well as LTP and cognitive deficits in the 5xFAD transgenic mouse model of Alzheimer’s disease (AD) early in the disease. Similarly, MT5 KO in neural cell cultures of 5xFAD mice and in iPS-derived neural cells of AD patients reduces neuroinflammation and the accumulation of neurotoxic products of APP metabolism. Most interestingly, we found that expression of mutated/truncated forms of MT5 in AD cell models reduces APP/amyloid pathology. Together, this suggests that pre-symptomatic AD pathology begin much earlier than expected and that MT5 modulation may alleviate this pathology. The underlying hypothesis is that mutant MT5 forms interfere with the detrimental mechanisms driven by endogenous MT5, thus preconfiguring MT5-based biomolecules with therapeutic potential for AD.

  • Objectives

To test this hypothesis, we plan three objectives to determine the therapeutic potential and the mechanisms of action of mutated forms of MT5 in: 1) Neural cell cultures from the 5xFAD mouse model of AD.

  • Human iPS-derived neurons carrying genetic mutations
  • 5xFAD mice at pre-symptomatic and symptomatic phases of the disease

Models: a) primary cultures of neurones/astrocytes from 5xFAD mice; b) human iPS-derived neurons with AD mutations; c) 5xFAD mice for in vivo studies

Techniques

MT5 activity will be modulated by transducing cultured cells and mouse brains with AAVs coding for MT5 mutated variants. We will assess the impact of these modulations using biochemistry (WB, immunoprecipitation, ELISA), molecular and cell biology (qPCR, mutagenesis, immunocytochemistry), advanced microscopy (SIM, HCS), electrophysiology (patch clamp), anatomopathology and mouse behaviour. Particular attention will be paid to pathways involved in the control of APP/amyloid metabolism, neuroinflammation and synaptic activity.

  • Expected results
  • Identify novel neurodegeneration pathways driven by MT5.
  • Set the basis for generating MT5-based biomolecules with therapeutic potential. – Take a further step to validate MT5 as a new potential target in AD.
  • Feasibility

The project is supported by 2 senior scientists and 2 technical staff. All the technical expertise and state-of-the-art equipment is available at the INP. The project is funded for 4 years by French national agencies (i.e., FRM, ANR).

  • Expected candidate profile

Be willing to learn (or already have a grounding in) one of the following areas:

biochemistry, molecular and cell biology, electrophysiology, microscopy or neuroanatomy of the brain. Theoretical knowledge of AD or at least neuroscience/neuropathology. Comfortable working with mice and a passion for scientific research. Ethical conduct, teamwork, motivation, curiosity and critical thinking skills.