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Cell Rep Med
Cell Rep Med
Cell Reports Medicine
2666-3791
Elsevier

S2666-3791(24)00404-X
10.1016/j.xcrm.2024.101683
101683
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A core proteome profile unites mouse models and patients in Alzheimer disease
Tsaka Grigoria grigoria.tsaka@kuleuven.be
1234∗
Rousseau Frederic 12
Schymkowitz Joost 12
1 Switch Laboratory, VIB Center for Brain and Disease Research, Leuven, Belgium
2 Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
3 Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
4 Leuven Brain Institute, KU Leuven, Leuven, Belgium
∗ Corresponding author grigoria.tsaka@kuleuven.be
20 8 2024
20 8 2024
20 8 2024
5 8 101683© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.

Levites et al. demonstrate that mouse models of Alzheimer disease (AD), exhibiting amyloid-beta (Αβ) plaque formation, share Αβ responsome proteins with humans. Their work underscores the value of these models in studying Αβ aggregation, cellular vulnerability, and early-stage AD pathology.
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pmcMain text

Mouse models for Alzheimer disease (AD) are inadequate as they lack tau-associated neurodegeneration. This, combined with a series of unsuccessful clinical trials, has led to criticism and even rejection of the amyloid-beta (Αβ) cascade hypothesis.1 However, recent clinical approval of Αβ-clearing monoclonal antibodies has shifted perspectives, demonstrating that Αβ aggregation is indeed a driver of AD pathology.2 The current understanding is that Αβ acts as an early trigger, leading to later-stage irreversible processes that cause neurodegeneration. Therefore, early intervention targeting Αβ could be key for more effective therapeutic and potentially prophylactic measures. Besides, the Αβ cascade hypothesis, as originally stated, is now considered overly simplistic. Recent evidence indicates that multiple variants of AD pathology exist.3,4 The cellular phase of AD is complex, affecting different cell types and brain regions in a specific, context-dependent manner.5 Too little is known still on the interactome and responsome of Αβ in AD, particularly in terms of how it determines cellular vulnerability and drives the transition from early-stage Αβ-dependent to later-stage Αβ-independent neurodegeneration.

While Αβ mouse models are incomplete, they do exhibit AD-like responses, including Αβ plaque formation, synaptic dysfunction, and memory deficits. These observations suggest that, despite their limitations, these models can still contribute to a more detailed understanding of early-stage AD pathology. However, an objective measure for assessing the utility of Αβ mouse models is still lacking. Here, Levites et al. conducted a longitudinal analysis of the Αβ responsome using deep proteomic analysis of the CRND8 APP695NL/F AD mouse model, comparing the findings to the 5xFAD mouse model and human AD symptomatic and asymptomatic patient-derived samples.6 The study revealed that the Αβ responsome varies with aging in mice, demonstrating differences between mouse models and humans, but importantly, a core Αβ responsome is common to all. Notably, matrix-associated proteins represent the most robust common Αβ responsome. These findings confirm discrepancies between human and mouse models but also suggest an objective measure for assessing the relevance of mouse models to human AD.

Several of these matrix proteins are present in plaques and in cerebral amyloid angiopathy lesions, dystrophic processes surrounding plaques, or in astrocytes. This indicates that the mouse responsome reproduces at least part of the complexity of the AD pathological portfolio. In addition, a small number of these proteins have been pathologically validated in human AD postmortem brains via immunohistochemistry. Furthermore, the overexpression of two of these proteins in the mouse brain increases Αβ aggregation, demonstrating the bidirectionality of the responsome: Αβ expression affects these proteins, and the presence of these proteins also influences Αβ aggregation. This suggests that mouse models remain useful for investigating the relationship between the Αβ interactome and mechanisms of cellular vulnerability.

All things considered, Αβ pathology and aggregation result from the molecular interactions of Αβ with its environmental components, which potentially include proteins, lipids, and nucleic acids. These interactions can facilitate Αβ aggregation, which in turn can lead to the functional alteration of its interaction partners, resulting in cell-specific dyshomeostasis and ultimately pathology. Our reviews have discussed such mechanisms, highlighting how heterotypic amyloid interactions can provide a framework for understanding the Αβ responsome.7,8,9 The current study makes several key findings.(1) The co-deposition of the responsome proteins in plaques is not homogeneous; some proteins are found in the periphery, while others are located in the core. Additionally, the composition of these proteins varies in plaques from different regions of the brain. This suggests that the longitudinal effect of the Αβ responsome could at least be partially reflected in plaques, allowing for the reconstruction of earlier and later events, as well as regional differences.

(2) Responsive proteins can influence Αβ aggregation without being incorporated into plaques. This suggests that the soluble proteome modulates Αβ aggregation, but the proteins involved are not necessarily the ones most functionally affected by Αβ pathology.

These findings echo the discovery of the enrichment of local Αβ homology to Αβ aggregation-prone regions in plaques, suggesting that at least part of the responsome could result from direct interactions between Αβ and its surrounding proteome early on in disease progression.10 This supports the ongoing significance of investigating the role of Αβ in neurodegeneration, improving the translational relevance of preclinical findings, and developing therapeutics targeting early-stage AD pathology. Finally, it will be of great interest to examine how the responsomes of humanized and mouse models correspond in terms of lipidomics and metabolomics. All in all, this work establishes a framework for understanding the changes occurring in AD human brain and offers an objective assessment of how well a model system mirrors the intricate proteomic changes in disease.

Acknowledgments

J.S. and F.R. are supported by the Flanders Institute for Biotechnology (VIB) KU Leuven and G.T. is supported by the Funds for Scientific Research Flanders (FWO) with the predoctoral fellowship 1163823N .

Declaration of interests

The authors declare no competing interests.
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References

1 Scheltens P. Blennow K. Breteler M.M.B. de Strooper B. Frisoni G.B. Salloway S. Van der Flier W.M. Alzheimer's disease Lancet 388 2016 505 517 10.1016/S0140-6736(15)01124-1 26921134
2 Cummings J. Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics Drugs 83 2023 569 576 10.1007/s40265-023-01858-9 37060386
3 Tijms B.M. Vromen E.M. Mjaavatten O. Holstege H. Reus L.M. van der Lee S. Wesenhagen K.E.J. Lorenzini L. Vermunt L. Venkatraghavan V. Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles Nat. Aging 4 2024 33 47 10.1038/s43587-023-00550-7 38195725
4 Ferreira D. Nordberg A. Westman E. Biological subtypes of Alzheimer disease: A systematic review and meta-analysis Neurology 94 2020 436 448 10.1212/wnl.0000000000009058 32047067
5 De Strooper B. Karran E. The Cellular Phase of Alzheimer's Disease Cell 164 2016 603 615 10.1016/j.cell.2015.12.056 26871627
6 Levites Y. Dammer E.B. Ran Y. Tsering W. Duong D. Abreha M. Gadhavi J.D. Lolo K. Trejo-Lopez J. Phillips J. Integrative proteomics identifies a conserved Ab amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease Cell Rep. Med. 5 2024 101669 39127040
7 Louros N. Schymkowitz J. Rousseau F. Heterotypic amyloid interactions: Clues to polymorphic bias and selective cellular vulnerability? Curr. Opin. Struct. Biol. 72 2022 176 186 10.1016/j.sbi.2021.11.007 34942566
8 Housmans J.A.J. Wu G. Schymkowitz J. Rousseau F. A guide to studying protein aggregation FEBS J. 290 2023 554 583 10.1111/febs.16312 34862849
9 Louros N. Schymkowitz J. Rousseau F. Mechanisms and pathology of protein misfolding and aggregation Nat. Rev. Mol. Cell Biol. 24 2023 912 933 10.1038/s41580-023-00647-2 37684425
10 Konstantoulea K. Guerreiro P. Ramakers M. Louros N. Aubrey L.D. Houben B. Michiels E. De Vleeschouwer M. Lampi Y. Ribeiro L.F. Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure EMBO J. 41 2022 e108591 10.15252/embj.2021108591
