Discoveries May Yield New Therapies for Alzheimer’s Disease and Dementia in Down Syndrome

New possibilities for treating Alzheimer’s disease and dementia in Down Syndrome (DS) patients-a currently untreatable condition-have been identified in two related discoveries by a University of British Columbia and Vancouver Coastal Health Research Institute (VCHRI) researcher.

A team led by Psychiatry Prof. Weihong Song has found that accumulation of a gene product, called Beta-site APP Cleaving Enzyme 1 (BACE1), is the molecular mechanism that produces the Alzheimer’s disease symptoms which affect virtually all DS patients in middle age. He also discovered that a related gene product, called BACE2, may be useful in treating Alzheimer’s disease and dementia in DS patients.The findings were published recently in two papers in the Federation of American Societies for Experimental Biology (FASEB) Journal.”Now that we’ve found the molecular mechanism that underlies development of Alzheimer dementia in DS patients, we have a new therapeutic target,” says Song, who is a Canada Research Chair in Alzheimer’s disease. “If we can suppress the activity of the BACE1gene- an established process called down regulating-then we can reduce plaque formation in Alzheimer’s disease and Down syndrome.”The incidence of Down syndrome is approximately 1 in every 700 births and the exact cause of Alzheimer dementia in Down syndrome is not known.Song’s group found that dementia symptoms in DS patients are caused by mature BACE1 proteins-a product of the BACE1gene-becoming “stalled” to produce an overabundance of amyloid beta protein. For reasons that are not yet understood, the proteins produced by BACE1 are not mobilised or trafficked through DS brain cells at a normal rate. They accumulate to create significantly higher levels of mature BACE1 proteins and ultimately, the amyloid beta proteins that produce characteristic Alzheimer dementia symptoms.The process for generating amyloid beta protein in Alzheimer’s disease involves a set of enzymes, called beta and gamma secretases, that function as molecular scissors. The secretases snip pieces off a longer protein to produce fragments of amyloid beta protein. Fragments that have been snipped, or cleaved, bunch up to create plaques.Scientists have known that BACE1 is a beta secretase key to this process, but the mechanism was not known until now. “Statistics show that 280,000 Canadians aged 65 and over have Alzheimer’s,” says Dr. Howard Bergman, Chair of the Canadian Institutes of Health Research Institute of Aging Advisory Board. “The discovery made by Dr. Song and his team is an important step towards the development of a new therapeutic approach to Alzheimer’s disease and dementia for people with Down’s syndrome.” Song-a member of the Brain Research Centre at UBC Hospital-says this discovery helped the research team overturn an existing theory about the cause of DS dementia. In a separate paper in the same issue of The FASEB Journal, Song focused on the role of the gene BACE2, previously understood to have a similar function to BACE1.Scientists had speculated that accumulation of BACE2 was implicated in producing DS dementia because the gene is located on chromosome 21. Down syndrome is caused by an extra copy of all, or part, of this chromosome.Song discovered that BACE2, despite its similarities to BACE1 (the beta secretase that produces amyloid beta proteins), does not contribute to DS dementia. Instead, it has the potential to treat the disease. He found that BACE2 cleaves amyloid precursor protein at a different site than was previously understood-within amyloid beta proteins. This cleavage precludes amyloid beta protein production outside the cell and the resulting development of neuritic plaques. “These findings turn previous ideas upside-down,” says Song, who is the Jack Brown and Family Professorship and Chair in Alzheimer’s Disease at UBC. “We now realise that if we stimulate production of BACE2 we may ultimately reverse plaque formation and have a new therapy for preventing Alzheimer’s symptoms.”(Source: Federation of American Societies for Experimental Biology (FASEB) Journal: University of British Columbia: July 2006).