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.

Keywords: Alzheimer's disease; amyloid beta; astrogliosis; neuroinflammation.

Figure 1.

Aβ production. In the amyloidogenic pathway (right), APP is cleaved by BACE followed by γ-secretase which releases Aβ peptides and APP intracellular domain (AICD), which generate the N and C termini of Aβ, respectively. In the non-amyloidogenic pathway (left), APP is cleaved sequentially by α-secretase and γ-secretase, which does not result in the generation of Aβ species.

Figure 2.

Cellular stress can trigger astrogliosis—increased numbers of reactive astrocytes, which are characterized by hypertrophy of processes. Astrocytes undergo many molecular changes when activated and can secrete a plethora of proinflammatory cytokines.

Figure 3.

A feed-forward mechanism of Aβ secretion by reactive astrocytes. Cellular stressors and proinflammatory cytokines upregulate APP, BACE and γ-secretase in astrocytes resulting in astrocytic Aβ production. In turn, this Aβ initiates further stress and inflammation driving subsequent Aβ production.

Figure 4.

In AD, neurons secrete Aβ, which activates resting microglia and astrocytes. In turn, activated microglia and reactive astrocytes secrete proinflammatory mediators, which may induce neuronal death. Additionally, neuroinflammation also induces APP and BACE1 expression in astrocytes resulting in further Aβ production.