Mechanism of Tau and ER Stress for Novel Alzheimer#s Disease Therapeutics

Alzheimer’s disease (AD) is a devastating disorder that currently affects an estimated 5.4 million Americans; this number is expected to increase to 16 million by 2050. We do not understand the biological processes that attack the brains of Alzheimer’s patients. Therefore, there is no cure for AD, yet. It is clear now that during Alzheimer’s progression, a protein called tau suffers an abnormal process that makes it dysfunctional and leads to its deposition inside brain cells. The brain of an Alzheimer’s patient shows severe cell death, which translates to progressive memory loss, dementia, and ultimately death. The initial step leading to the disease is unknown; however, we believe to have discovered the precise step that leads to cell death in Alzheimer’s. The endoplasmic reticulum (ER) is a cellular factory that hosts the machinery necessary for newly synthesized proteins to mature into their proper conformation. Recent results from our laboratory show that abnormal tau directly clogs the ER leading to its damage. This step initiates a cascade of events that cause the cell to die. Only in understanding this process we can unmask effective therapeutic targets for Alzheimer’s disease and related dementias. These drugs, in principle, will serve as effective therapeutics for AD patients.