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.
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