The role of astrocytes in amyloid production and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in the brain. It is thought that Aβ plaques trigger NFT formation, neuronal cell death, neuroinflammation and gliosis and, ultimately, cognitive impairment. There are increased numbers of reactive astrocytes in AD, which surround amyloid plaques and secrete proinflammatory factors and can phagocytize and break down Aβ. It was thought that neuronal cells were the major source of Aβ. However, mounting evidence suggests that astrocytes may play an additional role in AD by secreting significant quantities of Aβ and contributing to overall amyloid burden in the brain. Astrocytes are the most numerous cell type in the brain, and therefore even minor quantities of amyloid secretion from individual astrocytes could prove to be substantial when taken across the whole brain. Reactive astrocytes have increased levels of the three necessary components for Aβ production: amyloid precursor protein, β-secretase (BACE1) and γ-secretase. The identification of environmental factors, such as neuroinflammation, that promote astrocytic Aβ production, could redefine how we think about developing therapeutics for AD.

Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain

“…Astrocytic cell lines and human astrocytes respond with increased APP expression when exposed to TGFβ (Amara, Junaid, Clough, & Liang, 1999;Burton, Liang, Dibrov, & Amara, 2002;Gray & Patel, 1993), a cytokine which is associated with AD pathogenesis (Luedecking, DeKosky, Mehdi, Ganguli, & Kamboh, 2000). This implies that TGFβ increases Abeta levels in the AD brain by inducing APP upregulation in astrocytes (Frost & Li, 2017). In the neuroinflammatory context of AD, reactive astrocytes express higher levels of APP than resting astrocytes and, therefore, could produce more Abeta and contribute to amyloid pathology to a greater extent.…”

The role of gut microbiota in pathogenesis of Alzheimer's disease

“…(The function of astrocyte is the topic of another review. See the review; Frost and Li for detailed information).…”

What Is the “Relevant” Amyloid β42 Concentration?

“…By using Avogadro's constant of 6×10 23 , this can be converted to 330 fmol of Aβ42 generated by the human brain every second, or 28.5 nmol of it per day. This number is likely to be somewhat of an underestimation, because the human brain has a comparable number of glial cells, including astrocytes, that have been found to be capable of producing Aβ under certain conditions, such as stress . The number listed above should therefore be considered a conservative estimate, a lower boundary.…”

“…By using Avogadro'sc onstant of 6 10 23 ,t his can be converted to 330 fmol of Ab42 generated by the human brain every second, or 28.5 nmol of it per day.T his number is likely to be somewhat of an underestimation, because the human brain has a comparable number of glial cells, [14] including astrocytes, that have been found to be capable of producingA b under certain conditions, such as stress. [15] The number listeda bove should therefore be considered aconservative estimate, alower boundary.U nder healthyc onditions, accumulationa nd clearance are balanced, and sleep appears to play av ital role. [16] Disruption of Ab42 brain clearance can result in the accumulationo f synaptotoxic peptide concentrations ( % 50-500 nm)w ithin days or weeks.…”