DYRK1A is directly involved in phosphorylation of Tau proteins, which are core substrates to form pathologic fibrils in many debilitating neurological conditions including Alzheimer’s disease, Down’s Syndrome and other Tauopathies.
Historically, DYRK1A has been most well-known for its association with Down Syndrome where DYRK1A is overexpressed. Recent research increasingly points towards a link between DYRK1A overexpression and neurodegeneration including early-onset Alzheimer’s Disease which is frequently observed in Down Syndrome patients.
The association of DYRK1A with neurodegeneration is manyfold: DYRK1A phosphorylates tau, which contributes to the formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease. DYRK1A also regulates splicing and increases the ratio of 3R-tau over 4R-tau, which is observed in the brain tissue of Down Syndrome and Alzheimer’s Disease patients. Furthermore, DYRK1A was recently shown to increase the cleavage of amyloid precursor protein, leading to the formation of amyloid plaques. Thus, the formation of neurofibrillary tangles and amyloid plaques both converge on the DYRK1A target.
In addition to the histological aspect of neurodegeneration, DYRK1A may also play a role in neuroinflammation through the regulation of innate immunity. Chronic inflammation in the central nervous system is characteristic of neurodegeneration, with the involvement of cytokines IL-1, TNF-α, and IFN-γ, all of which can be suppressed by inhibition of DYRK1A.
Brickell’s novel platform of next generation DYRK1A inhibitors are blood-brain barrier- penetrating, making them prime candidates to convert a promising target into viable treatment options for patients with neuroinflammatory diseases.
Inhibition of DYRK1A and the subsequent reduction in tau phosphorylation and 3R-tau formation may be a potential promising treatment option for neurodegeneration in Down Syndrome as well as tauopathies including Alzheimer’s Disease and Pick Disease (Frontotemporal Dementia).
- Down Syndrome patients overexpress DYRK1A. Patients have a higher risk of developing early-onset Alzheimer’s disease; approximately 20% of Down Syndrome patients over the age of 45 have dementia, which is correlated with increased mortality.
- Alzheimer’s Disease affects 47 million people worldwide and is the most common cause of dementia, as well as a leading cause of mortality and morbidity in aging populations.
- Pick Disease (FTLD-tau) is characterized by the degeneration of the frontotemporal lobes, which causes dramatic changes in behavior, personality, and language abilities. It is one of the causes of early-onset dementia and can occur in patients as young as 20 years old. Notably, filaments in Pick disease contain only 3R tau isoforms, providing a good rationale for inhibiting DYRK1A in this condition.
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8. Penn Medicine Pick’s Disease Information