Therapeutic intervention in Alzheimer's disease

Alzheimer's disease (AD) results from a series of dysfunctions which spread throughout the cortex in a precise spatiotemporal manner, and which subsequently give rise to a characteristic pattern of cognitive and non-cognitive symptoms. Whilst some of these symptoms can be controlled with specific drug regimes, there are still no treatments available to prevent the disease. Similarly, there are no drugs available which will reverse or even halt the progression of the pathological changes which occur in the AD brain. It is hypothesised that ˜í‚â§-amyloid deposited within the brain as \plaques' causes slowly evolving physical damage to neurons which then triggers a stereotypical neuronal response to trauma. This involves specific cytoskeletal alterations which give rise to the characteristic neuropathology of AD and which can be experimentally modeled in both in vivo and in vitro models of neuronal injury. That the pathogenesis of AD crucially involves the cytoskeleton and that targeting these changes may be an effective method of delaying or even preventing neurodegeneration in AD was explored in this thesis. A number of broad hypotheses were posed. Firstly that there are significant cytoskeletal alterations in the AD brain which may be ameliorated by the use of cytoskeletal stabilising agents and which may subsequently limit the evolution of the neuropathological changes characteristic of AD. Secondly that metallothioneins may play a role in AD and perhaps be able to prevent the aberrant neuronal sprouting associated with AD. These hypotheses were addressed in a number of aims. The major conclusions from these investigations were that morphologically distinct plaque types differentially affect the architecture of the brain in the early and late stages of AD to result in significant cytoskeletal alterations. Similar observations were made following experimental cortical injury where it was demonstrated that the administration of cytoskeletal stabilising drugs can both prevent and delay the onset of neuropathological changes. Finally metallothioneins were shown to be upregulated in both the early stages of AD and following cortical injury suggesting that they may have a role in the pathogenesis of AD. This thesis has therefore demonstrated that it is possible to intervene in the sequence of events which ultimately leads to neurodegeneration in AD. Agents which target cytoskeletal alterations may represent alternatives to current therapeutic strategies."