Project title: Innovative strategy for Alzheimer disease: targeting neuroinflammation and DYRK/CLK kinases
is funded by UEFISCDI under the PN-III-PM Programme.
Acronim: ALZNEKIN
Project code: PN-III-P3-3.1-PM-RO-FR-2016-0040
Contract number: 93/BM/2017
Beneficiary institution: Grigore T. Popa University of Medicine and Pharmacy Iasi
Funding period: 01.05.2017-31.12.2018
Total amount: 39.055 lei
Romanian Partner: „Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania
Project leader: Prof. Univ. Dr. Lenuta Profire
Romanian Research team:
Asist Dr. Apotrosoaei Maria,
Asist Dr. Vasincu Ioana Mirela,
Asist Dr. Vasincu Alexandru
Asist dr. Iacob Andreea
Asist dr. Constantin Sandra
PhD Confederat Luminiţa
PhD Pavel Loredana
PhD Sava Alexandru
PhD Focșa Alin
French partner: Institute of Organic and Analytical Chemistry (ICOA), University of Orleans, France
Project leader: Prof. Dr. Sylvain Routier
French research team:
Dr. Frederic Buron
Dr. Karen Plé
Dr. Pascal Bonnet
Dr. Stéphane Bourg
PhD Place Matthieu
Abstract project
Neurodegenerative diseases like Alzheimer’s disease, Parkinson, Huntington and amyotrophic lateral sclerosis are the main causes of long lasting disability, affecting more than ten million European Union citizens, a number that will probably double in the next decades. Their common feature is neuronal degeneration in certain central nervous system areas. The processes involved in neuronal death are: apoptosis, cellular oxidative stress, excitotoxicity and cerebral ischemic disorders caused by glutamatergic hyperfunction. The main role in the pathogenesis of Alzheimer disease is played by the accumulation of beta-amyloid (Aß), a peptide consisting of 36-43 amino acids resulted from the amyloid precursor protein (beta -APP) by a process of proteolysis, under the action of β and γ secretases. It is believed also, that oxidative stress plays an important role in the pathology of neurodegenerative diseases. It is not certainly know that oxidative stress is the trigger factor for neurodegeneration or it occurs as a side effect of other illnesses, but there is sufficient scientific data to support the involvement of oxidative stress in the development of cellular damage. Another important feature of the Alzheimer’s disease is the neuroinflammation mediated by the activation of the microglia and astroglia cells (astrocytes) which is an important source of oxidative stress by inducing the formation of superoxide anion. The inflammatory hypothesis consists in the accumulation of glial tissue around plates with a local response mediated by cytokines and acute activation of the complement cascade. This inflammatory response may cause the damage of neurons, with the exacerbation of the disease’s pathological processes. The aim of the research project was to develop an innovative strategy for the treatment of Alzheimer disease. This strategy should inhibit the kinases (tyrosine-kinase and protein-kinase) involved in the hyperfosforilation of the tau protein and formation of neurofibrillary aggregates as well as reduce the neuroinflamation and oxidative stress. The originality and the innovative character of the project are supported by the structure of the designed compounds –imidazotiadiazol derivatives, which have the theoretical premises to target two mechanisms of action: inhibition of the formation of neurofibrillary aggregates and reduce the neuroinflamation. The developed compounds were physico-chemical and biologic characterized based on establishinh the inhibitory effect on the kinase DYRK1A and CLK1, antioxidant and antiinflammatory effects.
Objectives of the project:
The aim of the research project was to develop an innovative strategy for the treatment of Alzheimer disease. This strategy should inhibit the kinases (tyrosine-kinase and protein-kinase) involved in the hyperfosforilation of the tau protein and formation of neurofibrillary aggregates as well as reduce the neuroinflamation and oxidative stress. Another important objectiv of the project was to increase and strengthen the research collaboration between romanian and french research teams.