Dr Cramer and her colleagues at Case Western Reserve University School of Medicine in Cleveland have discovered that the drug called bexarotene reverses the degenerative effects in the brains of mice that suffer the equivalent of Alzheimer's disease found in humans.
In the brain of Alzheimer's patients the most predominant anomaly is the presence of what is referred to as neuritic plaques and neurofibrillary tangles which are believed to lead to the disruption of normal brain activity and cell death that ultimately robs patients of the ability to remember and use reasoned judgment. The disease process proceeds at a slow and ultimately deadly pace.
The underlying mechanism for the disease remains elusive though there are numerous hypotheses that have been proposed to explain disease onset. What is well established, however, is the fact that the plaques result from the aggregation of the peptide – β-Amyloid (Aβ) - a peptide is a relatively small molecule made of a sequence of amino acids analogous to the structure of proteins. Aβ is a direct product of the fragmentation of a trans-membrane protein called amyloid precursor protein (APP). Trans-membrane proteins span the plasma membrane that encircles every cell. There is a protein complex associated with the cleavage of APP; one of the proteins in this complex is an enzyme, protease – γ – secretase; this enzyme is a necessary component for the effective cleavage of APP.
Furthermore, the modification – mutation – of three genes have been implicated in the autosomal-dominant form of Alzheimer's disease. These genes are responsible for the production of APP and two additional factors required for the function of protease – γ – secretase .
Aggregates of the Aβ peptide are suspected of causing dementia, as mentioned earlier, possibly by interfering with the appropriate communication between neighboring neurons in the areas of the brain affected. In spite of the ambiguity surrounding the exact etiology of Alzheimer's disease, the genetic association is unambiguous. For example, individuals with a single copy of the APOE-4 gene have a five-fold increased risk of contracting the illness.
Of great interest is the fact that Cramer and her associates have shown that administration of the drug bexarotene to mice with the murine version of Alzheimer's disease results in the increased expression of APO-E – a protein that is known to bind to Aβ, the subsequent rapid clearance of Aβ and , most importantly, the reversal of abnormal behavior in the diseased animals.
These findings are of immense interest. Whether or not these results can translate into effective treatment of human Alzheimer's patients is dependent upon extensive and carefully executed clinical trials given the many differences between the architecture of the human and mouse brain. There is, however, a cause for hope.