N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease.

Thomas A Bayer

doi:10.3389/fnagi.2021.710579

Abstract

The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.

Highlights

Even though the field of Alzheimer’s disease (AD) research has rapidly developed over the last decade, there is still a lack of disease-modifying therapies
A number of reports have discussed the dominant presence of N-truncated Aβ variants within amyloid plaques in AD and Down syndrome patients (Harigaya et al, 2000; Tekirian, 2001; Miravalle et al, 2005; Piccini et al, 2005; Jawhar et al, 2011; Bayer and Wirths, 2014), while others suggest that full-length Aβ1–42 is pathologically relevant (Haass et al, 1992; Näslund et al, 1994; Selkoe, 2001; Walsh et al, 2002)
The loss of NEP activity leads to enhanced levels of brain and plasma levels of full-length Aβ, the elevated half-life of soluble Aβ, and increased amyloid plaque pathology in the J9 mouse model of AD (Farris et al, 2007)

Summary

Introduction

Even though the field of Alzheimer’s disease (AD) research has rapidly developed over the last decade, there is still a lack of disease-modifying therapies. A number of reports have discussed the dominant presence of N-truncated Aβ variants within amyloid plaques in AD and Down syndrome patients (Harigaya et al, 2000; Tekirian, 2001; Miravalle et al, 2005; Piccini et al, 2005; Jawhar et al, 2011; Bayer and Wirths, 2014), while others suggest that full-length Aβ1–42 is pathologically relevant (Haass et al, 1992; Näslund et al, 1994; Selkoe, 2001; Walsh et al, 2002). The authors used immunohistochemistry with the verified N-terminal specific Aβ antibodies to stain post-mortem brain tissue from sporadic AD patients.

Results

Conclusion