Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients

Abstract

Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016. Expert opinion: Drugs in Phase III clinical development for AD include one inhibitor of the β-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aβ monoclonal antibodies (solanezumab, gantenerumab, and aducanumab), an inhibitor of receptor for advanced glycation end products (RAGE) (azeliragon) and the combination of cromolyn sodium and ibuprofen (ALZT-OP1). These drugs are mainly being tested in subjects during early phases of AD or in subjects at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The hope is to intervene in the disease process when it is not too late. However, previous clinical failures with anti-Aβ drugs and the lack of fully understanding of the pathophysiological role of Aβ in the development of AD, put the new drugs at substantial risk of failure.

Maysin and Its Flavonoid Derivative from Centipedegrass Attenuates Amyloid Plaques by Inducting Humoral Immune Response with Th2 Skewed Cytokine Response in the Tg (APPswe, PS1dE9) Alzheimer’s Mouse Model

“…Currently, the FDA approved few AD drugs, such as acetylcholinesterase inhibitors, N-Methyl-D-aspartate (NMDA) receptor antagonists, monoclonal antibodies for anti-Aβ, inhibitor for BACE, inhibitor for RAGE receptor and the combination drug of cromolyn sodium and ibuprofen [12]. In the past few decades, various natural compounds (phytochemicals and herbs), naturally occurring polyphenol (resveratrol, trans-3, 4', 5-trihydroxystilbene), and nutritional supplements (i.e., cinnamon extract and savory) with anti-oxidant and anti-inflammatory activities have shown potential as a beneficial counteractive approach to prevent Aβ neurotoxicity by inhibiting oligomeric formation, alternative counter measure of Tau malfunction as well as correcting memory impairment [13–16].…”

“…Moreover, we explored the potential anti-Alzheimer’s effect of a CG extract, in which Maysin and its derivatives could exert protective effects for neurons by inhibiting oligomeric Aβ42 aggregation and β-Secretase (BACE) and decreasing neuronal toxicity by using neuronal PC12 cells as an in vitro model [20]. BACE, a potential drug candidate was examined its functional advantage for early phase preclinical familial AD patients along with inhibitor of RAGE (advanced glycation end products) in a Phase III clinical development stage [12]. In this study, our findings indicate that the natural Maysin and its derivative flavonoid compounds in EA-CG extract significantly prevented AD pathogenesis.…”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Although the cognitive decline of AD subjects is not related directly to plaque burden (Tu et al, 2014), much of the current focus on therapeutics for AD has been on the development of monoclonal antibodies against Aβ or its aggregates, including the drugs aducanumab, gantenerumab, and solanezumab which are currently in phase III clinical trials (Panza et al, 2016; Cavanaugh et al, 2014). Interim results from double blind studies have suggested aducanumab reduces plaques and Aβ in human and AD mouse brain and slows somewhat the cognitive decline in humans (Sevigny et al, 2016).…”

[P1–193]: Do Anti‐amyloid Beta Protein Antibody Cross Reactivities Confound Alzheimer Disease Research?

“…Current immunotherapeutic approaches to target Aβ have used passive humanised antibodies to enhance removal of Aβ from the brain with the aim of slowing or halting the progression of AD [49]. To date these have had little success [49][50][51][52].…”

“…To date these have had little success [49][50][51][52]. Bapineuzumab, Table 1, is based on the monoclonal antibody 3D6 directed towards an N-terminal epitope and Solanezumab, directed at an epitope from the Aβ (13-28) central region [53].…”