Next-generation Alzheimer's mouse model created
Los Angeles: Scientists have developed a new genetically engineered lab rat that has the full array of brain changes associated with Alzheimer`s disease.
The new mouse model supports the idea that increases in a molecule called beta-amyloid in the brain causes the disease, according to the study published in the Journal of Neuroscience.
"We believe the rats will be an excellent, stringent pre-clinical model for testing experimental Alzheimer`s disease therapeutics," said Terrence Town, the study`s senior author from the University of Southern California Keck School of Medicine, Los Angeles.
Alzheimer`s is an age-related brain disorder. Pathological hallmarks of Alzheimer`s brains include abnormal levels of beta-amyloid protein that form amyloid plaques; tau proteins that clump together inside neurons and form neurofibrillary tangles; and neuron loss.
Additionally, glial cells - which normally support, protect, or nourish nerve cells - are overactivated in Alzheimer`s.
Plaque-forming beta-amyloid molecules are derived from a larger protein called amyloid precursor protein (APP). One hypothesis states that increases in beta-amyloid initiate brain degeneration.
Genetic studies on familial forms of Alzheimer`s support the hypothesis by linking the disease to mutations in APP, and to presenilin 1, a protein thought to be involved in the production beta-amyloid.
Researchers often use rodents to study diseases. However, previous studies on transgenic mice and rats that have the APP and presenilin 1 mutations only partially reproduce the problems caused by Alzheimer`s.
The animals have memory problems and many plaques but none of the other hallmarks, especially neurofibrillary tangles and neuron loss.
To address this issue, Town and his colleagues decided to work with a certain strain of rats.
"We focused on Fischer 344 rats because their brains develop many of the age-related features seen in humans," said Town in a statement by National Institute of Neurological Disorders and Stroke (NINDS) in the US.
The rats were engineered to have the mutant APP and presenilin 1 genes, which are known to play a role in the rare, early-onset form of Alzheimer`s.
Behavioural studies showed that the rats developed memory and learning problems with age. As predicted, the presence of beta-amyloid in the brains of the rats increased with age. However, unlike previous rodent studies, the rats also developed neurofibrillary tangles.
The researchers performed a variety of experiments confirming the presence of neurofibrillary tangles in brain regions most affected by Alzheimer`s such as the hippocampus and the cingulate cortex.
Further experiments showed that about 30 per cent of neurons in these regions died with age, the largest amount of cell death seen in an Alzheimer`s rodent model.