THE ALZHEIMER'S PLAQUES, TANGLES AND MEMORY DEFICITS MAY HAVE A COMMON ORIGIN - PART III: ANIMAL MODEL

Ming Chen

Department of Pharmacology and Therapeutics, University of South Florida , College of Medicine, Tampa, Florida 33612, and Medical Research Service (151), Bay Pines VA Medical Center, St. Petersburg, Florida 33744

Received 6/9/98 Accepted 6/17/98

4. FINAL REMARKS

Several lines of evidence reviewed here suggest that a possible route to create an animal model for sporadic AD might be by decreasing the intracellular calcium levels. Despite the controversies and unanswered questions, this route is worth considering. It also appears to us that a successful model for sporadic AD might be created by improving the existing ones that target various neurotransmitter receptors and calcium channels.

Compared to this route, some other current approaches may have intrinsic limitations. For example, APP mutant-based models have not developed neurofibrillary tangles; and a solely ApoE4-based model may not develop full AD pathologies within the animal's lifespan [late onset in humans (42)]. A successful presenilin mutant-based model, though will exhibit early and severe AD pathologies, would however be difficult to develop (requiring a "gene replacement" paradigm)(8,9), and may not fully represent the sporadic AD conditions (e.g., its overproduction of Aß42/43).

AD is manifested by cognitive impairments, hence this lesion should be considered as the primary criterium for model development and evaluation. It is of interest to note that while severe cognitive impairments have not been reported in most of the current "AD models" (1,5,6), some other models in which cognitive impairments are prominent (13-15,24-26), have not however been generally accepted as "the models for AD".

It is important to note that the animal model experiments can also be used to examine the current "calcium hypothesis", which proposes that elevated calcium levels are responsible for neurodegeneration in AD (23). This hypothesis can be tested by the administration of calcium agonists such as glutamate, estrogen, calcium channel activators (as a matter of fact, it is tempting to speculate that such models might mimic some conditions of SP). Presumably, these experiments can help to resolve the controversies around this key issue of AD research in the near future.

It should be kept in mind that the AD-type cognitive impairments, unlike many other human diseases which can be perfectly mimicked in animals, will not be fully and exactly reproduced in the models, because the higher intellectual function affected by AD is the monopoly of humans. For example, the loss of some long-term memories (e.g., the patient's own name) and logical thinking will be difficult to reproduce in rodents. Despite these limitations, an animal model that targets the early pathological lesion would allow hands-on studies on the biochemical and other aspects of AD in its dynamic progression. The model will also allow a screening of pharmaceutical compounds that may be able to compensate, perhaps more effectively than the current ones, for the deficient element, thereby offering a promise for the prevention or postponement of clinical AD in the aging population.