Kaji S, Berghoff SA, Spieth L, Schlaphoff L, Sasmita AO, Vitale S, Büschgens L, Kedia S, Zirngibl M, Nazarenko T, Damkou A, Hosang L, Depp C, Kamp F, Scholz P, Ewers D, Giera M, Ischebeck T, Wurst W, Wefers B, Schifferer M, Willem M, Nave KA, Haass C, Arzberger T, Jäkel S, Wirths O, Saher G, Simons M. Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis. Immunity. 2024 Nov 12;57(11):2651-2668.e12. Epub 2024 Oct 16 PubMed. Correction.
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Salk Institute
Kaji and colleagues use a variety of experimental approaches to demonstrate that, in the AD brain, lipid-associated ApoE is phagocytically internalized into microglia together with lower-order polymers of Aβ, and that ApoE facilitates the dense fibrillar aggregation of Aβ within microglial lysosomes. This co-internalized and co-aggregated ApoE/Aβ is apparently eventually deposited into dense-core plaques, since it is stained by the β-pleated-sheet-binding dyes (e.g., Congo Red) that identify these plaques. The findings of this paper add to the accumulating evidence that dense-core, highly-aggregated Aβ plaques do not form spontaneously within the extracellular spaces of the AD brain, but rather are assembled intracellularly—within the acidic environment of microglial lysosomes.
View all comments by Greg LemkeWashington University
This is a fantastic study from the Simons lab that brings together a lot of key observations into an attractive theoretical framework for how APOE and microglia conspire to form nascent amyloid fibrils to seed pathology. It begs the question of whether decreased receptor-mediated microglial uptake of APOE variants such as APOE2 or APOE3ch influences their ability to seed amyloid pathology.
Another question is, what is it about microglial lysosomes as opposed to other cell types that foments a fibrillogenic interaction between APOE and Aβ? Aβ and APOE can also be taken up and trafficked to lysosomes in neurons or astrocytes. Yet depletion of microglia prior to pathology has such a profound effect on amyloid burden.
Translationally, these findings further suggest that decreasing APOE expression might be a way to slow amyloid pathology, although this would need to be done very early. Potentially it could also suggest that diverting APOE uptake into other cell types could also be protective. This may explain why LDLR overexpression using a Prion promoter decreased amyloid pathology (Kim et al., Neuron, 2009), while upregulation of APOE receptors in microglia in this paper augmented aggregation.
View all comments by Jason UlrichUniversity of Washington
Genetics studies point to endo-lysosomal, immune, and lipid pathways as dysfunctional in AD, and many of these genes are highly expressed in glia. In this study, Kaji et al., perform an impressive amount of experiments to show microglial cells are necessary for Aβ seeding, exacerbated by APOE, and that this event is mediated from the microglial lysosome. The endo-lysosomal, immune, and lipid trafficking pathways are highly interrelated as lipids and immune mediators utilize vesicular trafficking.
This study highlights how events that converge at the lysosome can initiate some of the earliest events in AD pathogenesis. This lends weight to the idea that targeting this pathway therapeutically may be beneficial for mitigating some of the drivers of AD pathology. It also shows that the lysosome is more than just an organelle that degrades unwanted material, suggesting that it may also function as a signaling hub that can respond to stimuli such as interferon signaling. How this is mediated is still an open and intriguing question.
View all comments by Jessica YoungBaylor College of Medicine
The current work is built on the creation of a knock-in mouse model expressing a HaloTag-tagged APOE, thus allowing its in situ visualization and biochemical purification. Using this elegant system, coupled with various imaging modality and biochemical methods, the authors reveal the formation of APOE aggregates in microglia within the endo-lysosomal compartment. The aggregates serve as a co-factor to facilitate Aβ aggregation and also impinge on microglial inflammation and lipid metabolism. Overall, the finding adds further evidence supporting a critical role of the immune, lipid, and endo-lysosomal pathways in AD.
While the demonstration of APOE and Aβ aggregates in microglial lysosome is certainly exciting, it remains to be determined how the intracellular aggregates seed the extracellular plaques and to what degree it contributes to the overall Aβ pathology. In addition, given the prominent role of APOE genotypes in microglia lipid homeostasis and tau-induced neurodegeneration, as demonstrated by the multiple publications from the Holtzman group, it would be interesting to assess whether similar APOE aggregates also form in the microglial lysosome of tauopathy conditions.
View all comments by Hui ZhengWeill Cornell Medicine
Kaji et al. propose that fibrillar ApoE—likely forming in microglia lysosomes after internalization and delipidation of the lipid carriers—promotes aggregation of Aβ. The authors preaggregated HFIP Aβ by incubating a solution in PBS for 48 hours at 37°C, then fed this to microglial cell cultures. This Aβ preparation most likely included a mixture of soluble and aggregated Aβ species. Microglial cells internalized the Aβ, promoting aggregation in the presence of ApoE fibrils, and this effect was consistent across BV2, primary, and iPSC-derived microglia, reinforcing the reliability of the findings beyond iPSC models. Large aggregates could have resulted from soluble Aβ binding to pre-existing fibrils during cellular incubation in the endolysosomal compartment and/or extracellularly.
In their experiments, lipidated ApoE was internalized by microglial cells and incorporated into lysosomes at a higher rate than its unlipidated counterpart, which enhanced Aβ aggregation. It is, however, worth reflecting on the fact that apoE4 is poorly lipidated relative to their ApoE2 and ApoE3 counterparts (Hanson et al., 2013), which would imply a lower rate of internalization -and fibrillation- into acidic compartments.
The authors ablated the JAK/STAT pathway in microglia using baricitinib, a JAK/STAT1 inhibitor, and they observed a reduction in Aβ brain deposition. Baricitinib has also been shown to ablate the PI3K-AKT pathway in vivo (Hindam et al., 2024). We have found that primary microglial cells establish extracellular, sealed compartments onto large synthetic Aβ aggregates into which lysosomal contents are secreted. This mechanism, known as digestive exophagy, is mediated by the PI3K-AKT pathway (Apr 2023 conference news). It is tempting to speculate that the decreased Aβ aggregation in 5xFAD mice treated with baricitinib could be in part due to reduced lysosomal exocytosis of previously internalized fibrillar material by microglia towards extracellular Aβ deposits.
References:
Hanson AJ, Bayer-Carter JL, Green PS, Montine TJ, Wilkinson CW, Baker LD, Watson GS, Bonner LM, Callaghan M, Leverenz JB, Tsai E, Postupna N, Zhang J, Lampe J, Craft S. Effect of apolipoprotein e genotype and diet on apolipoprotein e lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 2013 Aug 1;70(8):972-80. PubMed.
Hindam MO, Ahmed LA, El Sayed NS, Khattab M, Sallam NA. Repositioning of baricitinib for management of memory impairment in ovariectomized/D-galactose treated rats: A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling pathway. Life Sci. 2024 Aug 15;351:122838. Epub 2024 Jun 17 PubMed.
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