Modified intrinsic excitability in transgenic mouse models of progressive beta-amyloidopathy

Alzheimer?s disease (AD) is devastating and frightening for both sufferers and their families. In its early stages, Alzheimer?s leads to memory loss and confusion; at its peak, it leads to a complete breakdown of mental ability as brain tissue degenerates and the electrical activity underlying brain function breaks down. We are living to ever greater ages and therefore are more likely to fall victim to AD. Research into what goes wrong with the brain in AD is therefore increasingly important. We can recreate some of the conditions that occur in the AD patient?s brain by genetically modifying mice. For example, we can produce mice that accumulate the toxic peptide beta-amyloid in their brain as they age. High levels of these peptides are a key feature of AD and are thought by most researchers to be key causative factor. Information in the brain is largely encoded by brief electrical signals (spikes) generated when individual nerve cells (neurones) become stimulated. These neurones are connected together in large networks, and it is these neuronal networks which are thought to process and store memories. Disturbances in such neuronal networks are thought to underlie many disorders of memory, including those in AD. We have recently been trying to understand the causes of these electrical disturbances in AD by studying mouse models that overproduce beta-amyloid. To do this we record the electrical activity of individual neurones in the hippocampus, an area of the brain crucial for memory. This recently allowed us to identifying striking changes to the shape, size and patterns of spikes in mouse models of AD. These changes result from a reduced flow of sodium ions across the cell membrane via specialised proteins called sodium channels. We believe that if such changes are paralleled in man they will contribute substantially to the cognitive deficits that are a hallmark of AD. Using AD model mice we propose to further investigate the relationship between the changes to electrical properties of the brain and the age-dependent over-production of beta-amyloid. This will allow us to compare our findings with other studies of disease progression in these mice We will also investigate how the changes to sodium channels and spikes are produced and will also use secretase inhibitor drugs, similar to those in clinical trails, to attempt to reverse the alterations to electrical activity that develop as our mice age.

Alzheimer?s disease (AD) is the major cause of dementia in the elderly. Our laboratory is interested in characterising neurophysiological deficits that arise in AD and understanding their causal mechanisms. To do this we apply a variety of electrophysiological methods to study of pre-clinical animal models of AD-related pathology. Much of our work employs transgenic mice which over-produce Abeta peptides, molecules that are widely believed to play a crucial role in the pathophysiology of AD. In recent years, work with such mice, by ourselves and others has begun to reveal significant disturbances to synchronous network activity in the cortex and hippocampus, brain structures with crucial roles in cognitive function. In vivo EEG recordings reveal network hyperexcitability in these areas, which in some laboratories resembles epileptic activity. It is proposed that these disturbed patterns of network activity are likely to contribute to cognitive dysfunction in AD. As well as performing our own in vivo recordings, we have been investigating cellular level neurophysiological factors that could be the cause of these disturbed patterns of neuronal activity. Our work has focussed on modifications to intrinsic neuronal excitability, an aspect of neurophysiology well known to contribute to network hyperfunction in epilepsy. Using patch clamp recording from CA1 pyramidal cells in hippocampal slices, we have identified robust changes to intrinsic neuronal excitability and action potential waveforms in 2 different Abeta overproducing mouse lines. We also used nucleated macropatch recordings to identify a ~50% loss of voltage-gated sodium currents from the cell bodies of these neurones; potassium currents were, in contrast, entirely unaltered. All of these changes were absent in young animals, and their presence seems to parallel Abeta burden since they arise earlier in the more aggressive PSAPP double transgenic line. This application requests funding to follow up these findings in much greater detail. Our goals include: 1) Generating a more detailed understanding of the timecourse with which both altered excitability and sodium current depression arise. 2) Determining if similar changes to those observed in pyramidal cells occur in GABAergic interneurones. 3) Establishing if the changes to either excitability and/or Na+ channels can be reversed by pharmacological interventions that reduce CNS amyloid load. 4) Using dynamic clamp to establish if altered sodium current levels are solely responsible for the altered intrinsic excitability. 5) Examining if related changes to excitability and ion channels levels are seen in the axonal or dendritic compartments.