Altered protein may contribute to Alzheimer's disease

NEW YORK, Dec 08 (Reuters Health) -- The discovery that a different protein controls a key brain enzyme in patients with Alzheimer's disease may lead to new ways to diagnose and treat this form of dementia, Harvard researchers report.

The team found that compared with normal brains, a different protein regulates the activity of cyclin-dependent kinase 5 (Cdk5) in the brains of patients with Alzheimer's disease, causing Cdk5 to become overactive. This leads to modification of a protein called tau, which accumulates in the neurofibrillary tangles characteristic of Alzheimer's disease.

"The mechanism for the development of neurofibrillary tangles is really poorly understood," lead author Dr. Li-Huei Tsai of Harvard Medical School in Boston, Massachusetts, told Reuters Health. "This study actually begins to provide a mechanism for how, at the beginning, the neurofibrillary tangles may form."

The Cdk5 protein is responsible for adding phosphates to other proteins, which alters their activity. It is normally inactive, and must associate with a partner protein called p35 to be active. The p35-Cdk5 complex is important for normal development and function of the brain, Tsai explained to Reuters Health.

Tsai and multicentre colleagues examined Cdk5 and p35 in human brain tissues from normal patients and patients with Alzheimer's disease.

In all but one Alzheimer's patient, they found a smaller protein that was related to p35, which they called p25. The amount of p25 was 20 to 40 times higher than the amount of p35, and the activity of Cdk5 was also increased. Neurons and many neurofibrillary tangles in Alzheimer's patients were positive for p25, but not p35.

The p25 protein is also located in different places in the cell than p35, which changes what proteins Cdk5 will encounter and phosphorylate, Tsai said. The p25-Cdk5 complex overphosphorylated the tau protein, unlike the p35 complex.

The complex also disrupted cell structure, and caused degeneration and death of nerve cells in culture.

In the December 9th issue of Nature, Tsai and colleagues suggest that p25 production and accumulation in the brain may contribute to the development of Alzheimer's disease.

"Apparently, under certain conditions, Cdk5 becomes, so to speak, 'out of control' because of the production of the p25 protein," Tsai said. "Whenever the p25 protein is produced, it's a bad sign."

Their next step is to look at what causes p25 production. "Definitely, we think that the mechanism for the cleavage of p35 and the production of p25 is absolutely important to understand (how Alzheimer's disease develops)," Tsai said.

In an accompanying editorial, Dr. Ekhard Mandelkow of the Max-Planck-Unit for Structural Molecular Biology in Hamburg, Germany, writes that the results "provide potential targets for diagnosis or therapy" for Alzheimer's disease, which he describes as "the main form of dementia in today's ageing population."