Is Alzheimer's Associated Amyloid Beta an Innate Immune Protein

There is now abundant evidence that chronic inflammation in the brain is central to the pathogenesis of Alzheimer's disease (AD) and that this is precipitated through accumulation of amyloid beta (Aβ) peptides. In this review, we first outline this evidence and how specific receptors on microglia and monocyte/macrophages determine whether extracellular Aβ peptides can be cleared through non‐inflammato‐ ry phagocytosis or instead result in pro‐inflammatory cytokine generation. Most efforts of treatment for AD so far have focused on reduction of Aβ levels (in particular neurotoxic oligomers of Aβ1‐42) in the brain. Recent findings suggest an alternative approach in which pro‐inflammatory responses to Aβ peptides are targeted to reduce injury. Most recently evidence has come to light that Aβ peptides resemble anti‐ microbial peptides which are part of the innate defense system against infection. Such peptides act both by directly inactivating pathogens, but also by modulating respons‐ es of innate immune cells, including phagocytes. Indeed, Aβ peptides, particularly Aβ1‐42, do inhibit a range of potential pathogens, including bacteria, fungi, and viruses. Coupling this with evidence linking chronic viral, bacteria, or fungal infection to AD suggests that production of Aβ peptides in the brain is part of an innate immune response which might normally be beneficial, but which leads to harm when it is chronic or uncontrolled. This suggests that discovery of the original possibly infectious (or other inflammatory) stimulus for Aβ production would allow early intervention to prevent development of AD.