Forsøksdyr: The relationship between CSF biomarker microdialytes in an AD transgenic model and memory


Godkjenningsdato 22.10.2018

Alzheimer's disease (AD) is a progressive disease that causes degradation of memory, cognition, behavior, and the ability to perform daily activities. AD is inherently difficult to diagnose, especially in early stages when memory impairment is mild and may go unrecognized. To elucidate the molecular basis of pathological processes in AD, several AD mouse models have been developed. Most of these models exhibit transgenic expression of one or more gene mutations found in familial AD. These mouse models provide a powerful tool for investigating the molecular basis of cognitive decline associated with AD, and many behavioral paradigms have been applied to evaluate cognitive function in these model animals.

The major pathological hallmarks of AD are the loss of neurons, occurrence of extracellular plaques, as well as intracellular neurofibrillary tangles (NFT). Plaques are primarily composed of amyloid beta-protein (Abeta), which is produced from the amyloid precursor protein (APP) by sequential proteolytic cleavages. Although the clinical symptoms of AD are frequently diagnosed in older age, the degenerative process starts many years before the clinical onset of the disease.

Despite intense investigation into the mechanisms of neurodegeneration and possible causes of AD, currently no cure or definitive underlying cause exists. However, altered concentrations of Abeta peptide and Tau protein in the cerebrospinal fluid (CSF) are thought to be predictive markers for AD. In humans, these biomarkers are present decades prior to the onset of other symptoms in AD.

This application covers the sampling of CSF data from mice (mus musculus, n=50) in order to longitudinally compare sampled Abeta and Tau protein levels to behavioral performance in a memory task that is known to depend on brain regions implicated in AD. The work described in this application is intended for rodent research only; however, we are collaborating with researchers conducting an analogous study sampling CSF from human AD patients, and we ultimately aim to compare our animal findings directly with those in humans.

The well-being and health of the animals employed in these experiments will be continuously monitored, and they are not expected to experience pain or distress during the experiments. The transgenic animals will receive humane-endpoints if their phenotype affects general well-being. Surgery will be conducted under a strict anesthesia and analgesia regime that will eliminate distress and pain during surgery, and careful post-operative care will be employed to ensure that animals experience minimal discomfort. The sampling of CSF is optimal in awake, behaving animals, and therefore these experiments cannot be conducted in vitro. Extensive preliminary in vitro experiments will ensure that the CSF replaced in animals is highly similar, and will reduce the number of animals used. Moreover, these experiments cannot be conducted in invertebrates as they lack the brain structures of interest. Through the perfection of surgical techniques and limitation of duration, as well as number of surgeries, the severity of these experiments will be reduced.