Alzheimer's

There is no...good animal model for the [Alzheimer's] disease process characterized by a loss of cognitive functions and memory decline.-- Dr. D. Lindholm (Uppsala University), Journal Neural. Transm., Suppl., 1997:49, 33-42, Review.

Alzheimer's is the fourth cause of death in the United States and is presently a hot field of study. In 2001, it was estimated that 83,200 Canadians, whose age is 65 or over, would be expected to develop dementia; 50,500 would be women and 32,700 would be men. Also, 364,000 Canadians over 65 have Alzheimer's disease or related dementia; 247,520 are women and 116,480 are men. Worse, by 2031, over 750,000 Canadians will be expected to have Alzheimer's disease or related dementia. The disease is characterized by a progressive loss of cognitive functions in aging patients, such as loss of memory, time, place orientation and the final stages of the disease leave the patients dependent on caregivers. The neuropathological features include the presence of senile plaques and neurofibrillary tangles (NFT) accompanied by neuronal loss and deposition of extracellular amyloid beta in the brain. Due to the possible pathogenic processes leading to a common clinical representation of the disease, animal models have been created but failed to reproduce all the symptoms of the human disease. This is the reason why in the past decade mice with AD-like defects were created to mimic at least some of the neuropathological changes, cellular abnormalities and therapeutic targets occurring in AD patients.

In those animals having a deficiency in the neurotransmitter acetylcholine, lesions were created including many acute manipulations of the brain such as electrocoagulation, use of chemicals (excitotoxins) and transections of the nerve bundles in a specific region of the brain.(2) However, none of these pseudo animal models express the neuropathological characteristics such as senile plaques, and NFT found in the brain of patients. In amyloid beta-peptide (Ab) related animal models, the neurotoxic effects of Ab-peptide in vivo was not observed in rodents and primates although it is the paradigm of Alzheimer's disease. Nevertheless, scientists have used a continuous intra cerebral vascular (icv) injection of important doses of Ab but behavioral studies (e.g. spatial reference memory and passive avoidance) failed to demonstrate an important deficit and conclusions were based on behavioral tests usually performed on rodents and controversial due to their lack of validity. It is well known that abundant amyloid deposits can occur in cognitively normal individuals and such deposits correlate poorly with the presence of signs of dementia, which suggests that extra-cellular Ab is not the main and initial cause of the disease but rather a consequence of it. Again, transgenic mice with a deletion of the gene encoding the amyloid precursor protein (APP), from which Ab is produced, were created and showed partial AD-like neuropathology. However, no neuronal loss, the hallmark of the disease was observed while overexpresion of the wild type (i.e. the normal protein) or mutant protein increased some AD-like features such as learning deficits.

Other transgenic mice with a deletion of the gene encoding presenilin (PSI) did not show amyloid plaques and neuronal loss. Other results demonstrated that the regulation of APP in human neurons, which is thought to play a critical role in the disease, differs considerably from those reported in cultures of rodent neurons or in continuous cell lines. Ab is more abundant in human neurons than in rodent neurons and the APP metabolism leading to such increase seems to be restricted to our species and specifically to human brain cells. (3) Another significant difference in the metabolism of APP between species lies in the observation that protein kinase C is enrolled in important biochemical reactions, and increases the processing of APP into Ab in contrast to the protein kinase C-mediated decrease of Ab in rodent neurons. Clearly, and in addition to an evolutionary point of view, the data provides evidence that the assumption according to which the biology of rodents and humans or other primates depend on the same molecular and cellular events is wrong. There are major exceptions to an arbitrary rule that biologists have imposed following a series of lucky historical accidents in the labs and on which they built their working hypotheses. That makes research easier conceptually and practically but by no means it is relevant to human medicine. A rat is not like a monkey, which is not like a human being; cell types do not express the same molecules and do not necessarily have the same biochemical pathways. The reality is indeed much more complicated than this carbon duplicate of biological mechanisms across species.

Another important finding has recently drawn the attention of the biomedical community working in the billion-dollar field of research on Alzheimer's. The technology enabling the production of millions of transgenic animals has overshadowed past animal models quickly and excited the interests of many workers. As is it often the case, the simpler explanation is often the best and when it comes to treating a severe disease, the focus is on the strategy that is the most straightforward. Generally, vaccines offer such avenues in a sense that they are based on the ability of the body to participate in the immune response. Then, by boosting the body's own capacity to be involved in the fight against invaders or traumatic injuries, vaccines exploit the natural defenses in a natural and physiological way. That is why the engineering of vaccines is seducing. At the beginning of the research of a vaccine that could prove efficient to reverse the symptoms, transgenetic mice (Tg APP) were vaccinated with fibrillar Ab and the authors observed a reduction of Ab deposition and also cognitive impairments affecting memory and learning. The stage was set to envision the possibility that, since mice are like "small furry" humans, it would be possible that the same promising results obtained in animals be reproducible in humans. Criticism stormed before the trial even started and rebounded more when it was observed that Ab could cross the blood brain barrier(acting as a filter between the brain and the blood circulation)and form toxic Ab deposits. In addition, autoimmunity was not observed in the vaccinated mice, or was underestimated, but it did occur in human patients with deleterious effects.(4)

Even Dale Shenk and colleagues at Elan Pharmaceuticals (San Francisco - California) had based their therapeutic strategy on the paradigm that Alzheimer's was caused by extracellular deposition of Ab, which indeed might be intracellular. A vaccine was developed that caused the body to create antibodies directed against Ab, according to a mechanism of action that is still hypothetical. However, Elan Pharmaceuticals and American Home Products (U.S.A.) decided to pay the bill to be the first to develop a vaccine that, if safe and efficient, would have won the US$6 billion market expected by 2008: the golden geese. CEO Richard Dixey of Phytopharm (U.K.), who has been developing a vaccine was quoted in a February 2001 Nature Biotechnology paper. He said that the industry struggled to create an animal model of Alzheimer's in which the formation of amyloid plaques must go with dementia-like symptoms.(5)Despite the previous inability to create a model for Alzheimer's disease, the difficulty to measure objectively cognitive deficits in mice and the impatience of shareholders, who put their money in research, there was a strong desire for launching a trial that was based on poor science right from the onset. Eventually the trial started and was called AN-792. The trial, undergoing phase II in 360 patients and supported by Wyeth-Ayerts, the company probably best known for producing Premarin, was stopped when people started getting sick and developing encephalitis, an inflammation of the brain. Within days of announcing the termination of the trial, the company's share value went down by 70% and Elan was on the verge of being the next Enron. There were side effects that some scientists said could have been anticipated.

All in all, the use of animal models has been of little use for the very symptoms of the human disease (i.e. Ab deposits accompanied by cognitive impairments in addition to almost undetectable NFT in such animals) cannot be reproduced. These negative results make it difficult to establish causal relationships. Furthermore, epidemiological studies indicated that the prevalence of AD after age 65 is three times higher in women than men, which suggests that gender is a risk factor and underlies a more complex etiology of the disease. Back to the bench, scientists have ovariectomized rats to observe a possible potentiation on Ab-induced working memory deficits. They concluded to a potential neuroprotective role of estrogens in Ab-induced neurotoxicity. It was an observation already made in humans several years earlier. Currently the treatment is based on acethylcholine inhibitors, which address the symptoms but not the cause of Alzheimer's disease. However, this category of drugs already brings in 1 billion dollars a year.

1. Canadian Study of Health and Aging Working Group. "Canadian Study of Health and Aging: study methods and prevalence of dementia." Canadian Medical Association Journal, 150: 899-913 (1994)

2. Kiyofumi Yamada and Toshitaka Nabeshima. "Animal models of Alzheimer's disease and evaluation of anti-dementia drugs." Pharmacology & Therapeutics 88, 93-113 (2000)

3. Andrea C. Leblanc and Cynthia G. Goodyer. "Role of Endoplasmic Reticulum, Endosomal-Lysosomal Compartments and Microtubules in Amyloid Precursor Protein Metabolism of Human Neurons. Journal of Neurochemistry, 72: 1832-1842 (1999)

4. Liz Fletcher. "Vaccine tests key Alzheimer's disease's hypothesis." Nature Biotechnology vol. 19 February (2002)

5. Karen Birmingham and Simon Frantz. "Set Back to Alzheimer vaccine studies." Nature Medicine vol. 8 March (2002)