Neurodegeneration最新文献

Alzheimer's disease is associated with multiple neurotransmitter deficits, most importantly in the cholinergic system. There are also other pathological processes. Strategies to combat these are discussed.

Hybridization studies of mRNA link genetic with neurochemical and neuropathological approaches to Alzheimer's disease (AD). Here we review the distribution and abundance of amyloid precursor protein mRNAs in normal and AD-afflicted brains. The expression of apolipoprotein E and presenilin mRNAs are also discussed.

Dementia results from a combination of structural and neurochemical pathologies. The most reliable index of cognition in both postmortem and biopsied AD brain is synapse loss.

The present study describes ultrastructural changes in the ciliary ganglia of the cat and monkey following preganglionic axotomy. At 3, 5 and 7 days after operation, the nucleus of some neurons was irregular, with prominent indentations, and displaced to the periphery of the neuron. The surface of most neurons was irregular. Neurofilaments and glycogen-like granules were much increased in some neurons. At 21 and 28 days after operation, neurons again appeared normal. Dendritic profiles, packed with many mitochondria and glycogen-like granules, could often be observed from 3 days after operation. In longitudinal section such profiles represented expanded trunks of dendrites; dilated mitochondria and dense bodies were sometimes encountered within them. At later stages after operation, some of these profiles were synaptically contacted by, or closely associated with, axon terminals. In myelinated axons, mitochondria and glycogen-like granules were also increased in number and dilated profiles and dense bodies were found within the axoplasm. In unmyelinated axons, dilated profiles and myelin-like figures were present, as were vesiculo-tubular structures and dense bodies. Electron-dense and -lucent changes could both be observed in myelinated and unmyelinated axons. Almost all the axon terminals were affected 3 days after operation. Within such degenerating axon terminals, the synaptic vesicles had accumulated to form one or several clumps, sometimes the degenerating axon terminals had undergone filamentous hyperplasia. At 45 days after operation, hardly any axon terminals were encountered. Non-neuronal cells, including satellite cells, macrophages and Schwann cells, were actively involved in removing degenerating axons and other cell debris.

Both altered energy metabolism and oxidative stress have been proposed to contribute to tissue damage in neurogenerative diseases. Animal models and cell culture studies provide evidence for a role of these processes in several forms of neuronal death. Reductions in the activities of some key mitochondrial enzymes have been found in autopsied brain in Alzheimer's disease. However, results obtained with biopsied brain tissue as well as assessments of metabolic rates for glucosein vivoindicate that a reduced functional capacity of mitochondria is probably not a general feature in the brain in Alzheimer's disease. These studies do not address the possibility that short-lived changes in energy metabolism affecting a small number of cells at any one time could be contributing to cell death. Several findings point to a moderate increase in oxidative damage in those areas of brain which are most severely affected in this disease, probably resulting from an increase in production of reactive oxygen species. Whether this is a contributor to neurodegeneration or a consequence of it remains unresolved.

Recent evidence suggests that the neurochemical pathology of Alzheimer's disease includes severe disruptions of the neurotransmitter receptor/G-protein mediated phosphatidylinositol hydrolysis and adenylyl cyclase signal transduction pathways. The present article briefly reviews evidence from postmortem studies describing disruptions to these systems and speculates as to the importance of these changes in terms of contributing to disease pathology and limiting the success of neurotransmitter replacement strategies.

Behavioural and psychiatric problems in dementia are clinically important; they are also theoretically interesting. Neurochemical factors are likely to play a causal role in some of these problems. Two approaches to investigating the biochemical basis of behavioural problems are outlined: the correlation of prospectively collected behavioural data with postmortem neurochemical measures;and the detailed analysis of behaviour allowing investigation of underlying mechanisms. These approaches are illustrated with empirical data. David Bowen's neurochemical approach to dementia provided stimulus to this work.

Loss of the large pyramidal cells of the association neocortex and hippocampus, along with plaques and tangles, is fundamental to the neuropathology of Alzheimer's disease. The extent of Alzheimer-specific cell loss, relative to controls, is age-dependent with maximal losses in younger subjects though, because of the (additive) effects of ‘normal’ ageing on such cells, theabsoluteloss remains constant at all ages. The cause of the cell loss remains unknown but probably relates to neurofibrillary degeneration through a crowding out of organelles and a disruption of intracellular transport; oxidative stress may also contribute. The degree of clinical dementia correlates well with the extent of pyramidal cell loss.

Neurochemical studies of post-mortem human brain have made a major contribution to understanding the neuronal basis of neurodegenerative disease and formed the basis of rational therapies for such disorders. The application of this approach to the neurochemical pathology of Alzheimer's disease was pioneered by David Bowen. By combining assessment of post-mortem tissue (where the disease has usually run its full course) with tissue obtained ante-mortem (where the disease course is incomplete), it has been possible to (1) establish which neurones are lost in the disease, (2) determine which neurones are lost early in the course of the disease, and (3) discern which changes relate with the symptomatology of the disease. Thus, loss of cholinergic, noradrenergic and serotonergic innervation to the cortex occurs at an early stage, since markers of the neurones are lost in both post-mortem and ante-mortem tissue. By contrast, dopaminergic innervation remains intact and markers of cortical GABAergic interneurones are affected in post-mortem tissue only, suggesting that loss of GABAergic neurones occurs only at a late stage of the disease. Cholinergic markers and the number of pyramidal cell perikarya correlate with the severity of dementia, suggesting that loss of cholinergic and EAA neurones is the major contributor to the cognitive impairments of Alzheimer's disease. Loss of noradrenergic and serotonergic neurones probably contributes to the emergence of non-cognitive impairments in behaviour. Possible causes of selective neuronal loss are discussed.

In Alzheimer's disease the normal balance of metabolic pathways regulating trophic factors/cytokines is disrupted; local reduction may result in neurons being deprived of neurotrophic factors while an excess may initiate a cascade of interaction between glial cells and β-amyloid precursor protein metabolism thereby facilitating plaque formation. This paper briefly discusses the findings of our group on aspects ranging from cholinergic humoral and trophic factors to mechanisms underlying amyloidogenesis in Alzheimer's disease.