Preclinical to phase II amyloid beta (A_β) peptide modulators under investigation for Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer disease (AD) is the most common form of dementia and its incidence is increasing at an alarming rate all over the world. The pathophysiology of AD is characterized by chronic, progressive neurodegeneration which involves early synaptotoxicity. One of the most obvious pathological feature of AD is the accumulation of amyloid-β (Aβ) in the brain. Since current treatment options only provide symptomatic help and Aβ is thought to underlie early synaptic pathology, Aβ reduction or modulation in the brain may be a promising therapeutic strategy in preventing and /or reversing AD-related dysfunction.

Areas covered: This paper outlines and evaluates the current landscape of preclinical and clinical studies focusing on modulating Aβ pathophysiology. Data and analysis for this review were procured from PubMed, clinicaltrials.gov and Alzforum.

Expert opinion: According to current knowledge, reducing Aβ production offers numerous treatment options. However, targeting the initial steps by pharmacological interference with secretases is challenging due to the emergence of various side effects. The most promising approach seems to be the prevention of early Aβ oligomerization. Combination approaches targeting both Aβ and tau would seem to be another promising strategy that could have beneficial effects through the course of the disease.

KEYWORDS:

• Phase 0
• I
• and II trials related to AD
• amyloid-β
• monoclonal antibodies
• passive or active immunization
• aggregation inhibition
• PPARγ agonists and secretase inhibitor

Article Highlights

• There now seems consensus that neurotoxic β-amyloid (Aβ) is a major endogenous pathogen mediating very early steps in the development of Alzheimer’s disease (AD).

• Thus, beneficial treatment strategies imply that targeting Aβ pathology has to be approached at very early, even prodromal stages of AD.

• Two main requirements are crucial prerequisites for the achievement of those treatment options: the development of biomarkers for prodromal AD and appropriate compounds targeting Aβ processing.

• Targeting enzymes and substrates necessary for Aβ production might be problematic due to the cellular importance of APP as a signalling molecule and the hypothesized physiological role of Aβ, at least at low concentrations.

• More promising strategies seem to be (1) the prevention of early oligomerization steps attenuating the formation of toxic Aβ aggregates, (2) targeting the imbalance in trace element cations thereby inhibiting oligomer formation by inhibition via Zn2+ /Cu2+ chelation, (3) targeting particularly aggressive Aβ species and (4) the prevention of the interaction of toxic oligomeric species with target receptors /proteins.

This box summarizes key points contained in the article.

Declaration of interest

C.G. Parsons has acted as a consultant for Crossbeta Biosciences B.V. (Padualaan 8, 3584 CH Utrecht, The Netherlands). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Table 1. List of the current pharmacological armamentarium targeting Aβ pathophysiology of AD which provides in our opinion an appropriate overview of preclinical and clinical efforts designed to alter disease progression by manipulating the amyloid cascade in a variety of ways.

Additional information

Funding

This manuscript was not funded.