Researchers in the US have discovered how mutations in the presenilin 1 gene that causes early onset familial Alzheimer’s Disease disrupt an essential process for recycling protein, thus allowing toxins to build up and kill brain cells. They hope their discovery will spur new treatments for both the early onset and the more common late onset form of Alzheimer’s, a brain-wasting disease that affects millions of people worldwide.

A report of the study, led by Dr Ralph Nixon, professor in the Departments of Psychiatry and Cell Biology at New York University’s (NYU’s) Langone Medical Center, appears in the 10 June online issue of the journal Cell.

15 years ago, scientists discovered that the presenilin gene was commonly associated with the early onset familial form of Alzheimer’s, which can strike people in the 30s, but little was known about how it worked until this study, when Nixon and colleagues found that presenilin 1 plays a key role in “macroautophagy”, a process that digests and recycles unwanted proteins and is essential for neuron survival.

Nixon, who is also director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research, and director of the Center of Excellence on Brain Aging and the Silberstein Alzheimer’s Institute at Langone, told the press that:

“In mouse models of Alzheimer’s disease and in skin cells of patients with Alzheimer’s disease caused by presenilin mutations, we observed that the ability to break down and reuse normal proteins and to remove potentially toxic damaged proteins and organelles is severely impaired.”

He said this disruption kills nerve cells, whose loss does not appear to depend on the plaque build up of beta amyloid protein that is normally found in the brains of patients.

“Most of the drug development for Alzheimer’s has been focused on removing amyloid from the brain,” explained Nixon, who said their findings strongly suggest there are alternative target pathways:

“For example, therapies could be aimed at repairing the cellular mechanism that eliminates toxic proteins before they damage the brain,” he added.

Ongoing observations at the Nathan Kline Institute suggest a similar disruption of cellular protein recycling occurs in late onset Alzheimer’s, said Nixon, suggesting that other factors could also be involved.

So far, scientists have discovered over 160 rare mutations of presenilin 1 and two other genes cause the early onset familial form of Alzheimer’s, but have only found a few genes linked to the late onset form.

Nixon said there were currently no treatments to slow or prevent the progression of Alzheimer’s and he urged us to regard the disease as “multi-factorial and to approach the treatment from that perspective”.

“Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations.”
Ju-Hyun Lee, W. Haung Yu, Asok Kumar, Sooyeon Lee, Panaiyur S. Mohan, Corrinne M. Peterhoff, Devin M. Wolfe, Marta Martinez-Vicente, Ashish C. Massey, Guy Sovak, Yasuo Uchiyama, David Westaway, Ana Maria Cuervo, Ralph A. Nixon.
Cell, 10 June 2010

Source: NYU.

Written by: Catharine Paddock, PhD