Under the supervision of miklós jászberényi The physiopathology of Alzheimer’s disease and other neurodegenerative disorders Janique de vries Nejla jounaïdi Chloe marsollier Under the supervision of miklós jászberényi

NDD: an introduction Definition Neuro: neurones are affected, not necessarily in the brain but also throughout the whole body. Degenerative: The pathological processes lead to degeneration of neuronal tissue. Disease: “A disorder of structure or function in a human, animal, or plant, especially one that produces specific symptoms or that affects a specific location and is not simply a direct result of physical injury” (oxford dictionary).

NDD: an introduction Common pathological processes (e.g. protein misfolding & mitochondrial dysfunction). Different clinical outcomes. Photo source : ‪www.cannabisoils.ca

NDD: prevalence Alzheimer’s disease 2010: 35.6 million people worldwide* 2050: 115.4 million people worldwide* Parkinson’s disease >1/1000 people affected in Europe** Photo source : ‪www.nyas.org * 2010 report of ADI **European commission site

Questions What are the common characteristics of ndd ? What does the term implies concerning the patient’s prognosis ?

Common pathogenic features Alzheimer’s disease Genetic factors Abnormal protein aggregations Neuroinflammation Mitochondrial dysfunction Oxidative stress Excitotoxicity Apoptosis Fronto-Temporal dementia Prion diseases Huntington’s disease Amyotrophic Lateral Sclerosis Parkinson’s disease Spino Cerebellar Ataxias …

Protein misfolding - Hallmark of NDDs - « Proteinopathies » Alpha helices  Beta sheets - Aggregations Amyloid fibrils  Plaque deposits in CNS Impairment of cellular processes Common pathway of aggregation  common mechanism of neurotoxicity Photo source : http://www.intechopen.com/

Protein misfolding 2 mechanisms : Major consequences : Spontaneous conformation Induced conformation Different : Brain location Nerve cells repartition (ECR - ICR - Intra-nuclear) Major consequences : Interference with axonal transport Apoptosis Gliosis Inflammation Mitochondrial dysfunctions Controversial causal role Photo source : Nature Reviews - Neuroscience

Mitochondrial dysfunction Failure of OXPHOS  ATP depletion  cell death Abnormal OXPHOS  ROS  oxidative stress  cell death Mitochondrial damage  opening of mitochondrial permeability transition pores  loss of membrane potential & pH changes  further compromising of OXPHOS Release of mitochondrial proteins (SMACs)  binding to apoptosis inhibiting proteins  apoptosis

Mitochondrial dysfunction Photo source : "Role of Protein Aggregation in Mitochondrial Dysfunction and Neurodegeneration in Alzheimer’s and Parkinson’s Diseases" Hashimoto et al

The physiopathology of ALZHEIMER’S DISEASE And now, an example… The physiopathology of ALZHEIMER’S DISEASE

Aetiologies 2 protein abnormalities: Mitochondrial dysfunction: Αβ peptides  Senile plaques. Tau protein  Neurofibrillary tangles. Mitochondrial dysfunction: Oxidative stress  Tissue damage. Decreased glucose metabolism Photo source : American Health Assistance Foundation

Clinical aspects and treatments Sporadic AD. Familial AD. Progressive disease ⬄ Progressive loss of function. Cognitive and motor impairments. TREATMENTS NMDA antagonists. Cholinesterase inhibitors. AD = major focus of medical research. AD = major issue of public health.

Common features = therapeutic targets Conclusion Common features = therapeutic targets

Chloé M. Janique de V. Nejla J. THANK YOU FOR YOUR ATTENTION !