Reversal of Tau Pathology by an Adenosine A1 Receptor Antagonist

2018, 2020

The loss of memory at advanced age that is typical of Alzheimer’s disease begins silently and progresses steadily over a long period of time. During this time, protein clumps (amyloid plaques and neurofibrillary tangles) build up in the brain. The currently available drugs can only modestly slow down the failing memory, but they cannot reverse the process and bring memory back. Most work on animal models of AD confirms this seemingly irreversible progression of the pathology. However, there are exceptions: One is the discovery that certain drugs that bind to a class of adenosine receptors on neurons (ADORA1) can restore memory in transgenic mice that already have become demented. The likely reason is that the accumulation of clumped tau protein turns down energy production in neurons, and this is reversed by a specific blocker of ADORA1, rolofylline (Dennissen et al., 2016). We want to test this idea in different model systems: transgenic mice expressing a disease-causing mutation of tau protein, organotypic slices derived from these mice, and organoid slices developed from induced pluripotent stem cells (iPSC) from a human patient with tau pathology. The experiments are designed to reveal the mechanism by which the drug works, how the communication between neurons in the brain is affected by the energy crisis provoked by toxic tau protein, and how the ADORA1 blocker resolves the crisis by enhancing neuronal activity. We hope this leads to a new avenue for treatment of patients with Alzheimer’s disease.


Funding to Date

$575,000

Focus

Drug Discovery, Pathological Pathways and Systems

Researchers

Eva-Maria Mandelkow, M.D., Ph.D.



Eckhard Mandelkow, Ph.D.