Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease

Abstract

Despite more than a century of research, the aetiology of sporadic Alzheimer's disease (AD) remains unclear and finding disease modifying treatments for AD presents one of the biggest medical challenges of our time. AD pathology is characterized by deposits of aggregated amyloid beta (Aβ) in amyloid plaques and aggregated tau in neurofibrillary tangles. These aggregates begin in distinct brain regions and spread throughout the brain in stereotypical patterns. Neurodegeneration, comprising loss of synapses and neurons, occurs in brain regions with high tangle pathology, and an inflammatory response of glial cells appears in brain regions with pathological aggregates. Inheriting an apolipoprotein E ε4 (APOE4) allele strongly increases the risk of developing AD for reasons that are not yet entirely clear. Substantial amounts of evidence support a role for APOE in modulating the aggregation and clearance of Aβ, and data have been accumulating recently implicating APOE4 in exacerbating neurodegeneration, tau pathology and inflammation. We hypothesize that APOE4 influences all the pathological hallmarks of AD and may sit at the interface between neurodegeneration, inflammation and the spread of pathologies through the brain. Here, we conducted a systematic search of the literature and review evidence supporting a role for APOE4 in neurodegeneration and inflammation. While there is no direct evidence yet for APOE4 influencing the spread of pathology, we postulate that this may be found in future based on the literature reviewed here. In conclusion, this review highlights the importance of understanding the role of APOE in multiple important pathological mechanisms in AD.

Keywords: APOE; Alzheimer's disease; Apolipoprotein E; glia; inflammation; neurodegeneration; tau.

Figure 1

PRISMA flow diagram summarizing the review process. Template edited from 10. Papers referenced in the main body of text were identified through our systematic search and can be found in Table S3.

Figure 2

Amyloid‐β pathology in APOE3/3 and APOE3/4 carriers in normal ageing and AD. Aβ plaque deposition is evident in aged controls (A) and is exacerbated in the presence of the APOE4 allele (B), resembling an AD‐like phenotype. Both APOE3/3 and APOE3/4 AD cases (C and D, respectively) have substantial Aβ deposition in all six layers of the cortex. Images taken from the grey matter of inferior temporal lobe (Brodmann area [BA] 20/21). Information about all participants donated tissue can be found in Table S4. Aβ is stained with 6F/3D (mouse monoclonal, DAKO, M087201‐2, 1:100, 98% formic acid, 5 minutes). Scale bar 1 mm.

Figure 3

Tau pathology in APOE3/3 and APOE3/4 carriers in normal ageing and AD. In aged controls, phosphorylated tau species are absent in APOE 3/3 cases (A) and rarely found in APOE3/4 cases (B). In AD, both APOE3/3 (C) and APOE3/4 (D) have markedly increased numbers of tau‐positive neurones. Images taken from the grey matter of inferior temporal lobe (BA20/21). Phosphorylated tau is stained with AT8 (mouse monoclonal, ThermoFisher, 1020, 1:2500). Scale bar 50 μm, insert scale bar 25 μm.

Figure 4

Activated microglia (CD68) in APOE3/3 and APOE3/4 carriers in normal ageing and AD. The lysosomal marker of microglia and macrophages, CD68, shown in AD (C‐D) and age‐matched control cases (A–B). Various microglial morphologies can be observed, for example, ramified (A and D) and amoeboid (B and C) in both ageing/AD and APOE3/x. Images taken from the grey matter of inferior temporal lobe (BA20/21). Microglia are stained with CD68 (mouse monoclonal, DAKO, M0876, 1:100, citric acid antigen retrieval). Scale bar 100 μm, insert scale bar 25 μm.

Figure 5

Activated astrocytes in APOE3/3 and APOE3/4 carriers in normal ageing and AD. Glial fibrillary acid protein (GFAP) is a cytoskeletal protein in activated astrocytes. Activated astrocytes are seen in both ageing (A–B) and AD (C‐D), but more pronounced astrogliosisis is observed in AD. In AD, astrocytes express more GFAP in the cell bodies, thus appearing darker, especially in APOE3/4 cases (D), and have more processes (C–D). Images taken from the grey matter of inferior temporal lobe (BA20/21). Astrocytes are stained with GFAP (rabbit polyclonal, DAKO, 0334, 1:800). Scale bar 200 μm, insert scale bar 100 μm.

Figure 6

APOE at the interface of inflammation and neurodegeneration via glial‐mediated mechanisms. Microglia and astrocytes expressing APOE4 promote parenchymal gliosis and release pro‐inflammatory signals that are potentially associated with synaptic and neuronal loss. The paracrine signalling of microglial mediators along with the APOE‐TREM2 pathway induces a pro‐inflammatory phenotype, creating a vicious‐cycle of inflammation and neurodegeneration. Ineffective clearance of excess synapses by astrocytes in APOE4 mice allows accumulating levels of C1q that can act as a tag for synaptic elimination later in life.

Figure 7

Schematic diagram of pathological protein spread. While direct evidence for APOE influencing the spread of tau through the brain is lacking, the papers in our systematic literature search implicate APOE in many processes that could influence spread. These include synaptic transfer through the synaptic cleft (1), via nanotubes (2), by glial phagocytosis (3) or vesicular secretion (4 & 5).