A novel drug has been demonstrated to prevent the build up of amyloid plaques in the brain – a major contributor to the development of Alzheimer’s – providing promise as a treatment for the condition.
Amyloid plaques – clumps of misfolded proteins that build up in the brain – disrupt and kill neurons, which leads to the neurodegeneration of Alzheimer’s Disease. A team of researchers from University of California (UC) San Diego School of Medicine, Massachusetts General Hospital, and elsewhere, have identified a new drug that could prevent the condition by modulating a key enzyme involved in the formation of amyloid plaques.
Senior author, Steven Wagner, PhD, professor in the Department of Neurosciences at UC San Diego School of Medicine, said: “Alzheimer’s disease is an extraordinarily complex and multi-faceted condition that has, so far, defied effective treatment, let alone prevention. Our findings suggest a potential therapy that might prevent one of the key elements of Alzheimer’s Disease.”
The findings have been published in the Journal of Experimental Medicine.
Tackling amyloid plaque build up
Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides, which are generated by enzymes called β-secretase and γ-secretase. These sequentially ‘cleave’ a protein called amyloid precursor protein onto the surfaces of neurons to release Aβ fragments, some of which are particularly prone to forming plaques., The production of these plaques is elevated in patients with mutations predisposing them to early-onset Alzheimer’s Disease.
The use of drugs that inhibit either β-secretase or γ-secretase has been attempted to help prevent or treat Alzheimer’s Disease, however, many of these drugs are highly toxic or unsafe for use.
Wagner and colleagues investigated the therapeutic potential of drugs known as γ-secretase modulators or GSMs, which instead of inhibiting the enzyme, altering its activity so that it produces fewer Aβ peptides.
In animal models researchers found that repeated, low doses of the GSM eliminated Aβ42 production, a fragment particularly prone to misfolding, without causing any toxic side effects, and in macaques, was able to reduce Aβ42 levels by up to 70%.
In the mouse model of early-onset Alzheimer’s Disease, treating the animals either before or shortly after they began to form plaque build-up, the novel GSM decreased plaque formation and reduced plaque-associated inflammation, suggesting that the drug could be used prophylactically to prevent the disease.
Co-author Rudolph Tanzi, PhD, professor neurology at Harvard Medical School and director of the Genetics and Aging Research Unit at Massachusetts General Hospital, said: “In this study, we have pharmacologically characterised a potent GSM that, based on its preclinical attributes, appears to equal or exceed the potency of any previously tested GSMs.
“Future clinical trials will determine whether this promising GSM is safe in humans and could be used to effectively treat or prevent Alzheimer’s disease.”
