The Hidden Role of Non-Canonical Amyloid beta 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.