Alzheimer's Assocation Research only
All of alz.org
  • Go to Alz.org
  • Research Center
  • AAIC
  • ISTAART
  • Journal
  • Grants
  • TrialMatch
  • Press
  • Donate
  • Contact Us
Home
Science and Progress
Clinical Trials
Funding and Collaboration
You can Help
Stay Current
Video and Resources

Text Size

Small text Medium text Large text

Sanjay W. Pimplikar, Ph.D.


Sanjay W. Pimplikar, Ph.D.
Associate Staff, Cleveland Clinic Foundation, recipient of a 2008 Investigator-Initiated Research Grant (IIRG), 2002 IIRG and 1995 Pilot Research Grant



Research focus


I entered the Alzheimer's disease research field more or less by accident. Trained as a cell biologist, I was interested in studying how proteins on the outer membrane of a cell reached their correct destination inside a cell. I decided to use amyloid precursor protein (APP) as a marker protein to study this transport process. During these investigations we realized that when APP is clipped by the enzyme gamma-secretase, a fragment called AICD (for “APP intracellular domain”) is able to enter the nucleus of the cell and change gene expression (some genes are “switched on” while others are “turned off”). Once I realized APP, a cell surface protein, could communicate with the nucleus of a cell in this fashion and that virtually nothing was known about AICD, I was hooked.

Impact of Association funding
Without the Association's support of my research program, I doubt that I would have pursued investigations of AICD. In fact, there is a good chance that without the Association's support I would not be doing Alzheimer's research at all.

APP intracellular domain (AICD) as a contributor to Alzheimer's


In the early years of AICD research, the attitude in the field oscillated between “AICD is inconsequential” to “AICD is not important.” There is still some skepticism about its biological function and controversy about how it affects gene expression. However, the thinking in the field is now changing with the realization that AICD is conserved through evolution (meaning that it is identical in a range of species, from humans to mice) and interacts with several proteins that control communication inside the cell. A number of groups have started to make important contributions to our understanding of AICD biology and how it governs signaling inside cells.

Using genetic engineering techniques, we created mice that had elevated levels of AICD to study the effects of AICD overexpression. We were surprised to see the mice exhibit Alzheimer-like pathological features without increased levels of beta-amyloid or beta-amyloid plaques. Moreover, these features appear in a time-dependent fashion. Our transgenic mice start producing AICD at about 2 weeks. Abnormal activation of glycogen synthase kinase, a protein linked to the tau tangles of Alzheimer's, is seen at age 2 months. At age 3 to 4 months, the mice undergo an abnormal process in which phosphate is added to the tau protein. At this age, we also see abnormal, seizure-like electrical activity in the brain and changes in neuronal circuits, the ‘wiring' of the brain that enables it to carry out various functions. Excess accumulation of insoluble tau and memory problems begin at 8 months, and neurons in the hippocampus of the mice start to die by 18 months. Thus, except for the development of beta-amyloid plaques (which are also found in non-demented individuals), the AICD transgenic mice seem to capture the essential pathological features of Alzheimer's.

We are now studying the underlying mechanisms that cause these pathological features, all of which occur in human Alzheimer's. Our latest findings suggest that inflammation in the brain is likely to be one of the pivotal events induced by AICD. We think that our observations in animals are applicable to human disease because we also find increased amounts of AICD in the brains of people with Alzheimer's. If further studies confirm that AICD is a significant contributor to human Alzheimer's, we must change our thinking about the therapeutic strategies developed to fight Alzheimer's. Current clinical trials focused on reducing levels of beta-amyloid have met, at best, with limited success. Although a number of factors could account for this, the continued failure of amyloid-focused strategies should prompt us to seriously consider other, non-amyloid causes of the disease. I am organizing a symposium at the 2010 Annual Meeting of the Society for Neurosciences to discuss these alternative mechanisms.

Moving research forward


I have been fortunate to receive significant funding from the Alzheimer's Association. It is not always easy to convince others of ideas that run contrary to the prevailing dogma. In my view, the fact that the Association funded my previous and current studies on AICD demonstrates the Association's willingness to support innovative but risky ideas that more traditional agencies are reluctant to fund. Without the Association's support of my research program, I doubt that I would have pursued investigations of AICD. In fact, there is a good chance that without the Association's support I would not be doing Alzheimer's research at all.

I love interacting with the national as well as the local chapter of the Association. In the dark days of research when nothing seems to be going right, it is their commitment to the cause of fighting Alzheimer's that keeps me going.