p73 Gene and Alzheimer's Disease

The latest issue of Neuron has this study which reveals that missing a particular gene (p73) increases the risk of AD. The Globe and Mail has the scoop here. A sample:

Canadian scientists have discovered that a particular gene appears to be essential for protecting the brain as people age and that missing one copy may boost the likelihood of developing Alzheimer's disease or other neurodegenerative disorders.

In a study of genetically altered mice, researchers at Toronto's Hospital for Sick Children determined that mice with only one copy of the brain-protective p73 gene – instead of the normal two copies – exhibited the physical and behavioural traits of Alzheimer's disease.

The rodents' brains contained tangles, which are believed to clog up the pathways between brain cells, impairing their ability to learn and remember. The animals' co-ordination was also affected.

“Those mice when they were young seemed to be just the same as mice that had both copies of the gene,” said co-principal author Dr. David Kaplan, a senior scientist in the cell biology program at Sick Kids.

“But when we aged the mice to ages equivalent to older people, say over 65 years of age, then the mice with one copy of the p73 gene started to show all the hallmarks of a very aging, very old human brain,” Kaplan said Wednesday from Israel, where he was attending a research meeting.

And here is the abstract of the paper in Neuron:

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/− mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/− mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/− neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

Cheers,
Colin