Alzheimer's disease: two experimental models

Abstract

Alzheimer's disease is the most common form of senile dementia, though its cause is unknown. Of the six principal hypothesised origins of the disease, two were examined experimentally. The cholinergic hypothesis proposes that Alzheimer's disease is caused by neuropathological damage to the nucleus basalis of Meynert (nbM), causing a subsequent global reduction in brain acetylcholine levels, which results in the observed loss of recent memory and subsequent behavioural symptomatology. To test this hypothesis, rats were injected with either 0.01, 0.03 or 0.06mg/kg scopolamine hydrobromide (a cholinergic muscarinic blocker) and tested on a non-spatial task of object recognition, nonmatching-to-sample. The highest dose of scopolamine produced a significant impairment on a retention interval of 60 sec on the task, but there was no evidence that the drug produced faster forgetting of the stimuli. The result suggests that the drug caused a general depression in performance which may or may not reflect amnesic properties. In contrast, simultaneous tests with the acetyl cholinesterase, physostigraine, indicated that increasing available acetylcholine might attenuate the effects of the retention interval. A series of control tests revealed that scopolamine and physostigmine had no effect on the motor activity of the animals. A second series of control tests indicated that the rats relied on cues from a variety of sensory modalities in order to perform the nonmatching task. The notion that a cholinergic dysfunction is sufficient to produce the symptoms of Alzheimer's disease is questioned. It is proposed that structural damage (perhaps to the limbic system) may be a more likely cause of this disease, rather than a specific cholinergic abnormality. The second part of this thesis examined the toxin hypothesis of Alzheimer's disease, which proposes that the disease is caused by the accumulation of aluminium in the brain. Accordingly, rats were administered 72 mg/kg aluminium hydroxide orally, for three months, and recent memory capacities were assessed over 20 and 40 sec retention intervals on the nonmatching-to-sample task. No effects of aluminium administration on memory were noted. Additionally, aluminium did not appear to have any effect on the motor activity of the rats, and no accumulations of aluminium were detected in the nbM, hippocampus, amygdala or neocortex of the animals. Various reasons for the failure to find either accumulations of aluminium in the brain or recent memory effects are outlined. Finally, the AF64A-treated animal is considered as an alternative to the scopolamine-treated animal model, and other possible causes of Alzheimer's disease are discussed – notably the genetic hypothesis; and the possibility that a combination of accumulations of brain aluminium with decreases in CAT levels may be responsible for the disease.