Mathys H, Boix CA, Akay LA, Xia Z, Davila-Velderrain J, Ng AP, Jiang X, Abdelhady G, Galani K, Mantero J, Band N, James BT, Babu S, Galiana-Melendez F, Louderback K, Prokopenko D, Tanzi RE, Bennett DA, Tsai LH, Kellis M. Single-cell multiregion dissection of Alzheimer’s disease. Nature, July 24, 2024 Nature
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University of Kentucky College of Medicine
This study provides a comprehensive Rosetta stone for a multiregional, multicellular data mining atlas for Alzheimer’s disease. Importantly, the authors identified molecular architecture and cellular subsets for cognitive resilience to AD pathology. Furthermore, GWAS-related AD genes were integrated in this dataset, which revealed regional and cell-type specific expression during AD progression. Major glial-enriched modules for astrocytes, oligodendrocytes, and microglia showed a diverse range of functional programs tethered to pathways including cholesterol biosynthesis, metabolism, DNA damage, immunity, and others. Microglia and astrocytes showed the largest DEGs for several GWAS-AD risk genes in regions with high neuritic plaque load and diffuse plaques. Neurons and oligodendrocytes showed larger differences for several GWAS-hits in regions associated with high NFT density.
The dataset underscores how pathological progression, via neuritic plaque load, tangle pathology, dense core or diffuse plaque deposition, regionally hits cell types differently at multiple stages of disease. The dynamic complexity of AD progression reinforces the multisystem failure and multicellular response to energy metabolism.
The glial system seems to play a key role in the pathological architecture in AD. Highly intriguing is the astrocytic response to cognitive resilience despite the pathological burden in prefrontal cortex but also other areas of the brain, and the pathways that emerged in this cell type. The authors identified CR-related genes (GPX2, HMGN2, NQO1, ODC1, encoding the rate-limiting step in polyamine biosynthesis) that increased in astrocytes and positively correlated with cognitive function and showed the least cognitive decline over time in individuals. The two metabolic pathways that were highlighted included choline production and polyamine biosynthesis, the latter of which our group has followed. This is interesting because both systems modulate transmitter function but also show versatility in other critical functions of the cell.
The polyamine system is tightly regulated under normal conditions, but can become activated during physical and emotional stress, trauma, inflammation, etc. This is known as the polyamine stress response (PSR). Both ODC and other catabolic enzymes launch to protect the cell; however, in the brain, the magnitude, recurrence, and type of stress will depend on whether the PSR becomes transiently activated or remains maladaptive, thereby feeding disease continuance.
It may seem that, under certain conditions, astrocytic activation of the PSR is beneficial under the chronic burden of global AD pathology. However, it would be interesting to learn how the protein expression, polyamines themselves, and their end-product metabolites play out in astrocytes, or on the whole. Our group has shown that the polyamine system becomes activated during tau deposition but can also modulate tau aggregation, microtubule polymerization, and cognition (Sandusky-Beltran et al., 2021; Sandusky-Beltran et al., 2019). Other groups show that polyamines improve cognition under healthy aging conditions and amyloid pathology (Schroeder et al., 2021; Freitag et al., 2020). Tau and amyloid independently activate the PSR, but the single-cell response to the pathology burden is something future studies should investigate (Xia et al., 2022; Vemula et al., 2019; Mein et al., 2022).
The role of astrocytes becomes complex, however. One report showed astrocytic activation to have two opposing roles in response to amyloid deposition: a beneficial one whereby inhibition of ODC1 boosts urea cycle, clears amyloid, reduces putrescine and toxic ammonia byproducts, and decreases GABA (improving memory impairment), versus a detrimental putrescine pathway (Ju et al., 2022). Even so, there are many examples in which polyamines benefit several of the pathway modules noted throughout the study.
The biology and astrocytic dichotomy warrant further research, but certain cell types could possibly be exploited for cognitive resilience in the presence of AD pathology. Understanding the downstream biology behind this new study and that of others could be fortuitous therapeutically.
References:
Sandusky-Beltran LA, Kovalenko A, Placides DS, Ratnasamy K, Ma C, Hunt JB Jr, Liang H, Calahatian JI, Michalski C, Fahnestock M, Blair LJ, Darling AL, Baker JD, Fontaine SN, Dickey CA, Gamsby JJ, Nash KR, Abner E, Selenica MB, Lee DC. Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology. J Clin Invest. 2021 Feb 15;131(4) PubMed.
Sandusky-Beltran LA, Kovalenko A, Ma C, Calahatian JI, Placides DS, Watler MD, Hunt JB, Darling AL, Baker JD, Blair LJ, Martin MD, Fontaine SN, Dickey CA, Lussier AL, Weeber EJ, Selenica MB, Nash KR, Gordon MN, Morgan D, Lee DC. Spermidine/spermine-N1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response. Alzheimers Res Ther. 2019 Jun 29;11(1):58. PubMed.
Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Müller M, Gschiel V, Ristic S, Tadic J, Iwata K, Richter G, Farzi A, Üçal M, Schäfer U, Poglitsch M, Royer P, Mekis R, Agreiter M, Tölle RC, Sótonyi P, Willeit J, Mairhofer B, Niederkofler H, Pallhuber I, Rungger G, Tilg H, Defrancesco M, Marksteiner J, Sinner F, Magnes C, Pieber TR, Holzer P, Kroemer G, Carmona-Gutierrez D, Scorrano L, Dengjel J, Madl T, Sedej S, Sigrist SJ, Rácz B, Kiechl S, Eisenberg T, Madeo F. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985. PubMed.
Freitag K, Sterczyk N, Schulz J, Houtman J, Fleck L, Sigrist SJ, Heppner FL, Jendrach M. The autophagy activator Spermidine ameliorates Alzheimer's disease pathology and neuroinflammation in mice. 2020 Dec 28 10.1101/2020.12.27.424477 (version 1) bioRxiv.
Xia D, Lianoglou S, Sandmann T, Calvert M, Suh JH, Thomsen E, Dugas J, Pizzo ME, DeVos SL, Earr TK, Lin CC, Davis S, Ha C, Leung AW, Nguyen H, Chau R, Yulyaningsih E, Lopez I, Solanoy H, Masoud ST, Liang CC, Lin K, Astarita G, Khoury N, Zuchero JY, Thorne RG, Shen K, Miller S, Palop JJ, Garceau D, Sasner M, Whitesell JD, Harris JA, Hummel S, Gnörich J, Wind K, Kunze L, Zatcepin A, Brendel M, Willem M, Haass C, Barnett D, Zimmer TS, Orr AG, Scearce-Levie K, Lewcock JW, Di Paolo G, Sanchez PE. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia. Mol Neurodegener. 2022 Jun 11;17(1):41. PubMed.
Vemula P, Jing Y, Zhang H, Hunt JB Jr, Sandusky-Beltran LA, Lee DC, Liu P. Altered brain arginine metabolism in a mouse model of tauopathy. Amino Acids. 2019 Mar;51(3):513-528. Epub 2019 Jan 2 PubMed.
Mein H, Jing Y, Ahmad F, Zhang H, Liu P. Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study. Int J Mol Sci. 2022 May 27;23(11) PubMed.
Ju YH, Bhalla M, Hyeon SJ, Oh JE, Yoo S, Chae U, Kwon J, Koh W, Lim J, Park YM, Lee J, Cho IJ, Lee H, Ryu H, Lee CJ. Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer's disease. Cell Metab. 2022 Aug 2;34(8):1104-1120.e8. Epub 2022 Jun 22 PubMed.
View all comments by Daniel C LeeUniversity of California, San Francisco
This study is a landmark in AD research because of its detailed cellular and molecular characterization of postmortem human brain samples. Previously, the same group published an snRNA-Seq database of hundreds of cases from one brain region. In this study, they used snRNA-Seq to create a multiregion atlas of cases free of pathology and at progressive AD stages, enabling the identification of region-specific and cell-type-specific changes associated with AD. Their goal was to map the molecular signatures of the most vulnerable neurons in AD and the glial signatures associated with resilience.
The identification of vulnerable and resilient cellular populations opens new avenues for research into neuroprotective strategies. This study not only introduces new findings but also confirms and amplifies previous literature, such as the vulnerability of RORB neurons (Leng et al., 2021) and the role of reelin signaling in conferring resilience (Lopera et al., 2023), which in turn also serves to lend further credibility to the study's approach.
Additionally, the attempt to validate results with RNAscope is a plus, as bioinformatic pipelines can sometimes produce erroneous results due to filtering and alignment issues. In sum, this paper and accompanied database represent a significant step forward in unraveling the complexities of AD. By providing a detailed map of cellular and molecular changes across different brain regions, it opens up new possibilities for targeted interventions and enhances our understanding of AD vulnerability at a granular level.
References:
Leng K, Li E, Eser R, Piergies A, Sit R, Tan M, Neff N, Li SH, Rodriguez RD, Suemoto CK, Leite RE, Ehrenberg AJ, Pasqualucci CA, Seeley WW, Spina S, Heinsen H, Grinberg LT, Kampmann M. Molecular characterization of selectively vulnerable neurons in Alzheimer's disease. Nat Neurosci. 2021 Feb;24(2):276-287. Epub 2021 Jan 11 PubMed.
Lopera F, Marino C, Chandrahas AS, O'Hare M, Villalba-Moreno ND, Aguillon D, Baena A, Sanchez JS, Vila-Castelar C, Ramirez Gomez L, Chmielewska N, Oliveira GM, Littau JL, Hartmann K, Park K, Krasemann S, Glatzel M, Schoemaker D, Gonzalez-Buendia L, Delgado-Tirado S, Arevalo-Alquichire S, Saez-Torres KL, Amarnani D, Kim LA, Mazzarino RC, Gordon H, Bocanegra Y, Villegas A, Gai X, Bootwalla M, Ji J, Shen L, Kosik KS, Su Y, Chen Y, Schultz A, Sperling RA, Johnson K, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT. Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med. 2023 May;29(5):1243-1252. Epub 2023 May 15 PubMed.
View all comments by Lea T. GrinbergUniversity of California, Los Angeles
This is an exciting resource and accompanying manuscript which demonstrates the critical importance of multiregional brain profiling to define molecular cellular phenotypes of brain disease. By sampling multiple regions at different stages of disease, the authors begin to provide a more complete view of what changes are local and what are distributed across the brain, and their relationships to each other.
Among the insights gained by sampling multiple regions, this expanded resource more clearly separates cellular molecular correlates with amyloid and tau pathology. Consequentially, the integration with AD risk genes identifies possible multicellular effects on disease risk involving microglial and astrocyte correlates to amyloid pathology, and neuronal and oligodendroglia correlates to tau pathology, which warrant further investigation. The analysis of resilience is particularly interesting, where changes in specific metabolic pathways among astrocytes in multiple brain regions was the strongest correlate to differential cognitive decline. The analysis both identified molecules with known established effects in model systems and new targets for future study.
Overall, the multicellular, multiregional insights gained through this study and related profiling studies are collectively changing our conceptualization of neurodegenerative disease. Continued work is needed to apply these efforts to remaining major questions, synergize across studies, and experimentally validate and translate the insights gained.
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