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

Abstract

Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With the exception of Aβ1-42 and Aβ1-40, 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 Aβ variants to microglia activation. First, the impact of Aβ receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various Aβ species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these Aβ variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect Aβ neurotoxicity. In sum, the data indicate that gene polymorphisms in Aβ-driven signaling pathways in combination with the production and activity of different Aβ 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.

Neurogenetics: Precision Medicine-Based Approaches to Neurological Disorders with an Emphasis on Addressing Alzheimer’s Disease and Schizophrenia

“…7 Microglia have the ability to detect the presence of Aβ in the brain. 8 When encountered with Aβ plaques in healthy cells, they become reactive, indicating they are responding to abnormal protein accumulation. 8 Microglia in which Aβ has a direct interaction expresses a range of Berkeley Pharma Tech Journal of Medicine | 17 structurally diverse molecules, including TREM2, CD33, CD35, etc.…”

“…8 Microglia in which Aβ has a direct interaction expresses a range of Berkeley Pharma Tech Journal of Medicine | 17 structurally diverse molecules, including TREM2, CD33, CD35, etc. 8 These receptors are responsible for recognition and response to Aβ. 8…”

Ultra-Early Screening of Cognitive Decline Due to Alzheimer’s Pathology

“…Aβ40 is more abundant whereas Aβ42 presents much higher toxicity and a greater aggregation tendency [28]. Compared with Aβ42, aggregates containing Aβ43 (a longer Aβ C-terminal variant) are more likely to induce cerebral Aβ deposition [29]. Longer Aβ variants (Aβ42 and Aβ43) tend to be detected in Alzheimer's disease patients, whereas shorter forms (Aβ37, Aβ38 and Aβ40) are more likely to be found in subjects with intact cognition [30][31][32].…”

Amyloid β Induces Hormetic-Like Effects Through Major Stress Pathways in aC. elegansModel of Alzheimer’s Disease

“…Interestingly, some studies have also indicated that Aβ can potentially act as an antimicrobial peptide, suggesting a protective role for Aβ (Deepak et al, 2016, Pastore et al, 2020). Extensive work seeking to identify how Aβ becomes toxic in the brain has pointed to certain Aβ isoforms, small oligomer intermediates, and Aβ localization as key determinants in toxicity (Busch et al, 2022, Gallego et al, 2022, Rosenblum, 2002). Despite these discoveries, the role of Aβ in AD is still unclear, creating a need for well-characterized, robust models.…”