Age-related changes trigger Alzheimer
AD is the most common form of dementia often diagnosed in people over 65 years of age. This incurable disease worsens as it progresses, and eventually causes death and its aetiology is unclear.Research indicates that AD is associated with plaques in the brain composed of abnormal amyloid beta (AB) peptide. Research on AD is mostly based on inherited (familial) AD where it was discovered that generation of abnormal AB triggers the disease. Familial AD is characterized by small increases in the ratio of AB42 versus AB40 peptide. However, the majority of AD cases are sporadic. It is not known whether aging, as a major risk factor for sporadic AD, affects AB generation as well. The EU financed the two-year SECRETASE AGING project with the goal to determine if age-related changes affect enzymes responsible for production of AB. The working hypothesis was that activity of the enzyme gamma-secretase, which is responsible for AB generation, is altered during aging in sporadic AD. In vitro studies on rat neurons during aging were carried out to determine the changes occurring in gamma-secretase. An increased modification of gamma-secretase was seen, triggering an AD-like change in the conformation and activity of this enzyme, leading to an elevated AB42/AB40 ratio. These observations were confirmed with experiments in the mouse model. This effect on AB protein mimics the characteristics of familial AD mutations. Researchers also investigated the effects of lipid composition of neuronal cell membrane on the activity of gamma-secretase. They found that some changes in membrane lipid composition correlated with the reduction of gamma-secretase-dependent AB generation. The changes are similar to those found in membrane lipid levels in AD. Project activities have revealed the significant role of gamma-secretase in AB changes and AD. As such, this enzyme could be targeted therapeutically or membrane lipid levels modified to treat familial and sporadic AD. This work has been published in the prestigious EMBO Molecular Medicine.
