- 128 Downloads
KeywordsAmyloid Inhibitors Amyloid Formation Substantial Neuronal Loss Functional Amyloid Memantine
At least 40 diseases are caused by proteins or peptides folding incorrectly and aggregating into amyloid fibrils or plaques, including Alzheimer’s disease, type II diabetes, Parkinson’s disease, Huntington’s disease, and the spongiform encephalopathies. The best-studied amyloid-based disease is Alzheimer’s, characterized pathologically by abnormally high levels of brain lesions (senile plaques), neurofibrillary tangles in dead and dying neurons, and elevated numbers of amyloid deposits in the walls of cerebral blood vessels. The major component of senile plaques is a small peptide of 39–43 amino acids called β-amyloid (Aβ). In vitro and in vivo evidence shows that soluble, oligomeric forms of Aβ have potent neurotoxic activity and are the primary causes of neuronal injury and cell death, rather than the larger fibrils and plaques that are more readily visualized. An obvious strategy to treat Alzheimer’s, and other amyloidoses, is therefore to interfere with amyloid aggregation, and ideally oligomer formation, by either breaking up oligomers or making them aggregate further into a less toxic form. Current well-established AD drugs are acetylcholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. They can only alleviate symptoms for a limited time.
Numerous structurally diverse organic compounds can inhibit or reduce the aggregation and toxicity of Aβ in vitro. Peptide inhibitors of amyloid formation are usually based around self-recognition elements within the target peptide, such as KLVFF (16–20) in Aβ, which can form amyloid in isolation. These can be modified to improve activity and other properties, such as resistance to protease degradation, by modifications including backbone N-methylation, replacement with d-amino acids, retro-inverso sequences, or adding additional groups.
Alternatively, it may be possible to prevent key steps within the amyloid cascade that leads to cell death, initiated by the key event of aggregation. For example, Aβ is produced from the amyloid precursor protein by cleavage by β- and γ-secretase enzymes. Secretase inhibitors will thus prevent production of Aβ, though as these enzymes have multiple substrates, side effects from their use is likely to be problematic. Alternatively, upregulation of amyloid degradation, such as by activation of α-secretase which cleaves Aβ, can remove the toxic peptide. Immunization with Aβ showed exciting results in a transgenic mouse, though a subsequent clinical trial had to be halted after a small number of patients developed meningoencephalitis. Nevertheless, vaccination remains a promising approach, either actively, where the body produces antibodies in response to modified Aβ, or passively, where antibodies are produced elsewhere and used therapeutically. Activated microglia, along with a range of inflammatory mediators, has been identified in association with the lesions of AD, implying that anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs could protect against the disease.
It is unclear why Aβ oligomers are toxic. Plausible mechanisms of toxicity include oxidative stress, metal binding, free radical formation, or ion channel formation, so it may be desirable to interfere with these processes, using reducing agents, metal chelators, or ion channel inhibitors. Using stem cells to replace lost neurons is a possibility for the future, though this approach would not remove the toxic material.
Despite intense research, no compound has been successful in clinical trials since memantine in 2002. Trials are therefore switching to patient groups at earlier stages of the disease, before substantial neuronal loss, despite difficulties in identifying these groups at risk.