The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer's Disease

Recent advances have placed the pro-inflammatory activity of amyloid beta (A beta) on microglia cells as the focus of research on Alzheimer's Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different A beta variants with variable length and chemical modifications. With the exception of A beta(1-42) and A beta(1-40), the biological significance of most peptides for AD is as yet insufficiently understood. We therefore aim to provide a comprehensive overview of the contributions of these neglected A beta variants to microglia activation. First, the impact of A beta receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various A beta species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these A beta variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect A beta neurotoxicity. In sum, the data indicate that gene polymorphisms in A beta-driven signaling pathways in combination with the production and activity of different A beta variants might be crucial factors for the initiation and progression of different forms of AD. A deeper assessment of their interplay with glial cells may pave the way towards novel therapeutic strategies for individualized medicine.

Automated summary

Recent research has focused on the pro-inflammatory activity of amyloid beta (Aβ) on microglia cells in Alzheimer's Disease (AD). There are over 100 different Aβ variants with variable length and chemical modifications, and their biological significance for AD is not fully understood, except for Aβ(1-42) and Aβ(1-40). This study aims to provide a comprehensive overview of the contributions of these neglected Aβ variants to microglia activation.