Renewal for the Alzheimer disease and Down syndrome treatment : targeting simultaneously kinases and neuroinflammation – RA2DoSt

Alzheimer’s Disease (AD) is a worldwide pandemic. This multifaceted, progressive neurodegenerative disease is characterized by progressive cognitive decline and memory loss and no solution is presently available for curative treatment. Specific mutations in APP or PS1 have been described representing a few percent of the AD cases. Duplication of APP have been also described but most importantly Down syndrome (DS) with a trisomy of human chromosome 21, where APP is located, is a major risk factor. Indeed all the DS patients will develop AD between the age of 40 to 80 years. Drugs that are currently in use or in clinical trials act selectively on polymer deposits, enzymes or inflammation. Since initial AD research efforts, certain enzymes, such as protein kinases, have been discovered to be involved in disease progression, as well as in the appearance of inflammation.
In AD a vicious circle starts when kinase expression and activity increase, leading to an accumulation of amyloid deposits and neurofibrillary tangles (Tau deposits) in the CNS. The body then responses with inflammation, which, instead of solving the problem actually increases it, ultimately leading to a run-away response. Developing treatment that addresses this enzyme over-expression and simultaneous inflammation is thus a highly relevant alternative. The leading laboratory in Orleans has recently discovered a new family of thiadiazoles that have been shown to inhibit both dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and dual specificity protein kinase (CLK1). Both of these enzymes are involved in AD progression via a beta and TAU deposits in the brain. It has also been shown that these types of compounds, through their structure and chemical properties, are able to decrease inflammation and Reactive Oxygen Species (ROS). DYRK1A encoded in the human chromosome 21. DyRK1A is a major driver of DS phenotypes in animal models and a drug target to improve cognition in DS patients.
To validate this innovative strategy, a consortium has been established to design selective dual DYRK1A/CLK1 inhibitors. Our project gives an unprecedented alternative, e.g. discovering agents able to diminish both and TAU polymer deposits and reduce inflammation under complementary mechanisms.
Furthermore, in vitro and in vivo tests will be carried out on the most promising compounds. ADME-Tox will also be performed in order to characterize the different biological effects that can affect the pathology, e.g. penetration through the blood-brain barrier, enzyme inhibition in CNS and potential to decrease the neuroinflammatory processes. Potential neuroprotective and anti-inflammatory effects will be evaluated in vitro on cellular models and in vivo in DS models at early stage to rescue cognitive deficit and at a later stage when AD starts. In addition PET imaging of transgenic mice affected will allow ro follow chronic amyloidosis, inflammation and any potential rescue.
The French partners (Orleans, Poitiers, Tours, and Strasbourg) will collaborate with external foreign partners (Iasi, Romania and Oxford, England) as well as with screening platforms (Lille, Roscoff, UK) to accelerate the time necessary to go from hit identification to lead optimization. It is noteworthy that our project involves PHENOMIM, a French national infrastructure who will support the work on animal DS and new DS-AD models. Their implication and the well-established validation of the planned in vivo tests will guarantee product and strategy valorisation.
This project should provide a better understanding of the phenomenon linked to kinase activity and how it is associated with neuroinflammation in AD. This will also offer interesting perspectives toward the treatment of other neurodegenerative diseases such as prion disorders in which the presence of these two biological phenomena has been highlighted by both neurobiologists and clinicians.