Amyloid-β

Amyloid-β

The amyloid-β (Aβ) is generated by sequential proteolytic cleavage of the transmembrane amyloid precursor protein (APP) by two membrane-bound enzymes, β- and γ-secretase.

The amyloid-β (Aβ), occurring within a growing family of amyloidogenic proteins, is a 40-43 amino acid peptide that accumulates in the central nervous system (CNS) plaques, which are a characteristic feature of such as Alzheimer's, , are associated with the aggregation and misfolding of amyloidogenic peptides.

The Aβ peptide is a cleavage product of amyloid-β precursor protein (APP), a transmembrane protein found in most cells of the body. When APP is cleaved via the non-amyloidogenic pathway by α-secretase, followed by γ-secretase, the resulting fragments are non-toxic. In the amyloidogenic pathway, APP is cleaved by the β-site APP cleaving enzyme (BACE1), followed by γ-secretase, producing Aβ peptides of differing lengths (e.g. Aβ1-39, Aβ1-40, Aβ1-42). In the brain, these peptides, particularly the longer Aβ1-42 peptides, are prone to aggregation into dimers and other multimers (believed to be neurotoxic), then forming oligomeric fibrils and eventually amyloid plaques. Normally, Aβ is cleared from the brain by enzymes, which cleave the peptide, or other proteins that help transport Aβ out of the brain, to prevent its accumulation.

Neuropathological findings of extracellular insoluble plaques of amyloid-β (Aβ) and intraneuronal neurofibrillary tangles (NFTs) are diagnostic of disease and are used to determine disease severity. Although the accumulation of insoluble Aβ peptides into plaques that are deposited throughout the brain is a hallmark of disease and is believed to trigger a cascade of pathologic events leading to progressive neuronal dysfunction, over the last two decades, further investigation has suggested that the fully-matured fibrils are no longer considered to be the main toxic agent; rather, soluble, oligomeric species of the Aβ peptide have been shown to better correlate with disease severity. Studies in several mouse models described three amyloid-β oligomers: amyloid-β trimers, Aβ*56 and amyloid-β dimers. A research suggested Aβ*56 might play a pathogenic role very early in the pathogenesis of Alzheimer’s disease.

There is a huge controversy aboutwhether amyloid-β (Aβ) is a proper therapeutic target for alzheimer’s disease, because none of the amyloidocentric drugs tested to date has met their predetermined primary endpoints. Critics of the amyloid theory see the failure of solanezumab, which was considered as a crucial test of amyloidocentric therapeutic approaches in the clinic, as the final test of the amyloid hypothesis for treating Alzheimer’s disease. But there are still many of the scientists involved in the AD studies who have not changed their view of the amyloid hypothesis, indespiteofthe setback with solanezumab.Four main approaches have been exploited to reduce levels of Aβ in the brain: prevention or reduction of Aβ formation, mainly by targeting two membrane-bound enzymes, β- and γ-secretase; removal of existing amyloid deposits through immunotherapy (passive or active immunization); prevention or reduction of Aβ aggregation; and enhancement of Aβ clearance.

, an oral BACE1 inhibitor, is now being investigated in a phase III study. Inhibition of Aβ production via cleavage of APP is an appealing strategy, but it has proved unsuccessful in therapeutic trials. After proteolysis of APP by β-secretase, , is a γ-secretase inhibitor and reduces Aβ in the brain, plasma and cerebrospinal fluid in vivo. Preclinical of BMS 299897 for Alzheimer's disease was discontinued in USA in 2013.

Passive and active approaches to immunization against Aβ could be envisaged to promote the immune-cell-mediated removal of Aβ peptides from existing amyloid plaques and halt or reduce their further accumulation. Solanezumab is a newer monoclonal antibody, which targets an epitope in the central region of Aβ and preferentially binds to soluble Aβ oligomers. Many researchers believe that Aβ plays a key role in AD pathology, but so far no amyloid immunotherapy has proven effective in slowing cognitive decline in AD patients. Released on 23rd Nov., 2016, Eli Lilly announced that the Phase 3 clinical trial of solanezumab failed to demonstrateefficacy in treating the diseasein recent clinical trials. "The failure of this trial is something that could be another step back for the amyloid theory," said Professor Bryce Vissel, Roth Fellow and Director of the Centre for Neuroscience and Regenerative Medicine at the University of Technology Sydney (UTS). And the failure of solanezumab bring Aβ immunotherapy into broadcontroversy. The lack of reliable biomarkers at early preclinical stages of AD and the complexity of measuring changes in cognitive and functional status in asymptomatic individuals pose a particular challenge to demonstration of clinically meaningful effects before clinical manifestation of the disease.Intervene the formation of oligomeric fibrils and aggregates of Aβ peptides, which are important components of amyloid plaques and might be involved in AD pathogenesis, may have therapeutic value for the treatment of AD. Preclinically, the Aβ anti-aggregation agent tramiprosate (homotaurine) reduced plaque load in animal models; however, in a large (n = 1,052, of whom 790 completed the trial) phase III trial,31 this agent failed to meet primary end points.

Despite two decades of intensive work, the amyloid hypothesis has not led to the hoped for therapeutic advances. This has caused some to question its validity and to ask whether efforts aimed at reducing Aβ synthesis are ever likely to be successful. The finding of a mutation in APP that protects against Alzheimer’s disease and reduces the production of Aβ suggests that it may be premature to write off the amyloid hypothesis. Moreover, the negative results of therapeutic trials should be interpreted in the light of evidence that Aβ deposition occurs early in the preclinical phase of the illness. The emerging paradigm of targeting treatments at asymptomatic high-risk individuals remains untested, but if this gains support, it will signal a sea change in the way in which Alzheimer’s disease is treated with a move from tertiary to secondary prevention.

References:

Ezio Giacobini, Gabriel Gold. Nat. Rev. Neurol. advance online publication 12 November 2013. doi:10.1038/nrneurol.2013.223

Judith R. Harrison, Michael J. Owen. The British Journal of Psychiatry (2016) 208, 1–3. doi: 10.1192/bjp.bp.115.167569

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