Cerebral amyloid angiopathy

The role of amyloid in Alzheimer's disease looks destined to rise from bit part to lead player with the publication of three papers in the July edition of Nature Medicine. Scientists from three centres have found new evidence that dearly implicates amyloid in the pathogenesis of Alzheimer's disease, as well as having devised a diagnostic test that seems to be fairly specific and created a potential new treatment for the disease.

One of the reasons that the precise role of fibrillar B amyloid has remained elusive, despite its undeniable presence in the brains of people with Alzheimer's disease, is that none of the experimental mouse models of the disease has exhibited the full range of pathological features found in human Alzheimer's disease. Transgenic mice that express amyloid precursor protein in the cerebral cortex do not seem to sustain neurological pathology, and little neuronal death occurs when rats are injected with quantities of amyloid similar to that found in an amyloid plaque. These findings seemed to show that amyloid is an important factor in Alzheimer's disease, but not the causative agent.

Changiz Geula and his colleagues at Harvard Medical School now suggest that one reason for these observations could be that Alzheimer's disease "may be specifically a primate disease, and that possibly we've been looking in the wrong place." By developing a primate model of Alzheimer's disease, Dr Geula and colleagues have now shown that not only is B amyloid present in Alzheimer's disease, but it is almost definitely causative (Nature Medicine 1998;4:827-32).

To test their hypothesis, Dr Geula and his team injected very tiny quantities of fibrillar B amyloid into the brains of rhesus monkeys. They were able to identify neuronal loss not only at the site of injection but also circumferentially around the centre of the injection. Injections of both soluble B amyloid and the solution used to carry the fibrillar form caused significantly smaller amounts of damage, demonstrating that it is the fibrillar B amyloid that kills neurones and not simply the act of injecting something into the brain.

In addition, Dr Geula's team observed that the injection of fibrillar B amyloid seemed to induce an intense microglial reaction in a halo around the site of the injection, in the same pattern found in Alzheimer's disease, and also induced hyperphosphorylated tau, the protein that forms neurofibrillary tangles in the brains of people with Alzheimer's disease. Thus the three hallmarks of Alzheimer's disease were identified in the rhesus monkey model, and furthermore, young primate brains revealed little neuronal toxicity, while older primate brains proved much more susceptible to fibrillar amyloid. Alzheimer's disease therefore seems to be both species and age specific.

Claudio Soto and his colleagues at the New York University Medical Center have also been working with B amyloid. They have been studying the process of how normal amyloid peptides are induced to fold up into the abnormal conformation of amyloid fibrillar sheets and have been using this information to try to find a way to stop it happening. They have created synthetic "B sheet breaker peptides," which are similar in molecular structure to B amyloid peptides but which seem to be able to prevent the formation of amyloid sheets and amyloid deposition in animal models (Nature Medicine 1998;4:822-6). In addition, they have gone on to show that these peptides can degrade preformed amyloid fibrils in animals (in press). Both of these observations point to a potential therapeutic approach to Alzheimer's disease.

The third breakthrough in this series is a potential new diagnostic test for Alzheimer's disease. Researchers from the Heinrich-Heine-Universitat in Dusseldorf, Germany, believe that they have identified a way to diagnose Alzheimer's disease while the patient is still alive. Although many potential diagnostic tests have shown to be promising in the past, to date none has proved specific enough to be useful.

The researchers used fluorescence correlation spectroscopy to identify single B amyloid aggregates in the cerebrospinal fluid of patients with Alzheimer's disease. With this technique a soluble fluorescent dye tags synthetic B amyloid peptide "probes," and when this solution is added to cerebrospinal fluid, the probes attach themselves to any single aggregates of amyloid sitting in the fluid. The tagged aggregates will fluoresce in a laser beam, sending a recordable signal, detected as a single flash.

Cerebrospinal fluid was taken from 15 patients with clinical Alzheimer's disease and compared with that from 19 patients who had other neurological diseases (Nature Medicine 1998;4:832-4). All 15 cases were picked up positive by fluorescence correlation spectroscopy; one case of cerebral amyloid angiopathy was also picked up. If the researchers can find a way to distinguish between amyloid aggregates derived from the brain parenchyma and those from blood vessels then it may be possible to refine the specificity of the test to distinguish between these two conditions, and to correlate the pattern of flashes with the extent of disease. These findings must first be confirmed in a larger group of patients.

RELATED ARTICLE: Tau protein linked to dementia

Although amyloid plaques are clearly significant in the pathogenesis of dementia, other factors are coming to the fore, writes Abi Berger. Tau protein--a major component of neurofibrillary tangles--has, until recently, been thought of as an innocent bystander, but is now known to be neurotoxic in its own right. Families with mutations of the tau gene can develop an inherited form of frontotemporal dementia, which is characterised by tau tangles, in the absence of amyloid plaques. Thus amyloid toxicity and abnormal tau are both implicated in dementia.

People with the greatest genetic susceptibility for late onset dementia are those carrying the apolipoprotein E4 gene. People who are homozygous for the gene are nine times more likely to develop Alzheimer's disease than those without the gene. They are also now known to have a high risk of atherosclerotic disease, so the gene seems to be a risk factor for both vascular and degenerative disease in the same individual. Recent research points to a possible cause arising from an interaction between the gene and infection with the herpes simplex virus.

COPYRIGHT 1998 British Medical Association
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