Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Johnson, Erik C. B.; Carter, E Kathleen; Dammer, Eric B.; Duong, Duc; Gerasimov, Ekaterina S.; Liu, Yue; Liu, Jiaqi; Betarbet, Ranjita; Ping, Lingyan; Yin, Luming; Serrano, Geidy E.; Beach, Thomas G.; Peng, Junmin; Jager, Philip L. De; Haroutunian, Vahram; Zhang, Bin; Gaiteri, Chris; Bennett, David A.; Gearing, Marla; Wingo, Thomas S.; Wingo, Aliza P.; Lah, James J.; Levey, Aĺlan I.; Seyfried, Nicholas T.

doi:10.1038/s41593-021-00999-y

Cited by 289 publications

(700 citation statements)

References 81 publications

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“…Here, we see evidence of a direct relationship between Pyk2 and MAPK1 activity, raising the possibility that Pyk2-mediated activation of MAPK1 may also lead to decreased Tau phosphorylation in PS19 0/+ animals. MAPKs, a family of kinases that also include JNK, have long been implicated in the pathogenesis of AD [ 77 – 80 ], and a recent large-scale proteomic analysis of postmortem AD brain tissue from the Accelerated Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium revealed significant enrichment for proteins related to MAPK signaling and metabolism that strongly correlated with cognitive decline [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy

Brody

Nies

Guan

et al. 2022

Mol Neurodegeneration

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Background Genetic variation at the PTK2B locus encoding the protein Pyk2 influences Alzheimer’s disease risk. Neurons express Pyk2 and the protein is required for Amyloid-β (Aβ) peptide driven deficits of synaptic function and memory in mouse models, but Pyk2 deletion has minimal effect on neuro-inflammation. Previous in vitro data suggested that Pyk2 activity might enhance GSK3β-dependent Tau phosphorylation and be required for tauopathy. Here, we examine the influence of Pyk2 on Tau phosphorylation and associated pathology. Methods The effect of Pyk2 on Tau phosphorylation was examined in cultured Hek cells through protein over-expression and in iPSC-derived human neurons through pharmacological Pyk2 inhibition. PS19 mice overexpressing the P301S mutant of human Tau were employed as an in vivo model of tauopathy. Phenotypes of PS19 mice with a targeted deletion of Pyk2 expression were compared with PS19 mice with intact Pyk2 expression. Phenotypes examined included Tau phosphorylation, Tau accumulation, synapse loss, gliosis, proteomic profiling and behavior. Results Over-expression experiments from Hek293T cells indicated that Pyk2 contributed to Tau phosphorylation, while iPSC-derived human neuronal cultures with endogenous protein levels supported the opposite conclusion. In vivo, multiple phenotypes of PS19 were exacerbated by Pyk2 deletion. In Pyk2-null PS19 mice, Tau phosphorylation and accumulation increased, mouse survival decreased, spatial memory was impaired and hippocampal C1q deposition increased relative to PS19 littermate controls. Proteomic profiles of Pyk2-null mouse brain revealed that several protein kinases known to interact with Tau are regulated by Pyk2. Endogenous Pyk2 suppresses LKB1 and p38 MAPK activity, validating one potential pathway contributing to increased Tau pathology. Conclusions The absence of Pyk2 results in greater mutant Tau-dependent phenotypes in PS19 mice, in part via increased LKB1 and MAPK activity. These data suggest that in AD, while Pyk2 activity mediates Aβ-driven deficits, Pyk2 suppresses Tau-related phenotypes.

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Section: Discussionmentioning

confidence: 99%

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy

Brody

Nies

Guan

et al. 2022

Mol Neurodegeneration

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“…When considering the products of the 196 genes assessed, 66 proteins with significant positive correlations between protein abundance and MMSE (mini-mental state exam) (p < 0.05; higher abundance correlated with better cognition) (Table S6) were identified in the ROSMAP and Banner (Banner Sun Health Research Institute) populations (Johnson et al, 2022). Johnson et al reported that modules “post-synaptic density” and “protein transport” were enriched in proteins correlated with resilience that were previously identified in another study (Johnson et al, 2022). In an analysis that directly compared protein abundance in AD vs AsymAD (individuals with AD pathology and without significant cognitive impairment) (Supplementary Table 2 in Johnson et al), 1,540 proteins had higher abundance in AsymAD (log2FC > 0 with adj.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, to identify proteins that shared resilience signatures in the human ROSMAP and Banner data set, data from Johnson et al (Johnson et al, 2022) was used (Supplementary Table 6, considering p- and bicor values for MMSE30). Proteins that were upregulated in AsymAD vs AD can be found in Supplementary Table S2 of that publication.…”

Section: Methodsmentioning

confidence: 99%

Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

Telpoukhovskaia

Hadad

Gurdon

et al. 2022

Preprint

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Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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“…Additionally, while the ROS/MAP dataset presented an opportunity to study the effects of rs16969968 on a background of an unusually-low smoking prevalence (Cornelius et al, 2022), future work would benefit from inclusion of a more diverse group of subjects with more robust assessment of smoking history. In terms of approaches, RNA sequencing data has been previously found to not fully capture the protein-level changes in AD brains, which were detectable through a proteomic analysis (Johnson et al, 2022). This limitation should be considered when interpreting the findings of our study, in which we utilized bulk and single-nucleus RNAseq from the prefrontal cortex.…”

Section: Discussionmentioning

confidence: 99%

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

Rybnicek

Chen

Milic

et al. 2022

Preprint

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Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to cognitive impairment in Alzheimer's Disease (AD). While preclinical work suggests a possible protective and cognitive-enhancing role for the auxiliary nicotinic α5 subunit, mRNA expression of the CHRNA5 gene has not been closely examined in the context of human aging and dementia. Here, we investigate the impact of two common SNPs predicted to have different effects on the nicotinic α5 subunit: the function-compromising rs16969968 and the expression-altering rs1979905. We analyzed data from human prefrontal cortex (922 subjects with matched genotypic and post-mortem RNA sequencing, including 22 subjects with single-nucleus data) of elderly participants in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We tested the impact of SNP haplotypes on prefrontal expression of CHRNA5 as well as that of SNPs in its receptor partners: CHRNA4 and CHRNB2. In the context of cognition and neuropathology, we observed a significant negative association between the high CHRNA5-expressing rs1979905A2 genotype and β-amyloid load in the prefrontal cortex. Our analyses revealed that the greatest abundance of CHRNA5 expression was in chandelier neurons, a sparse but disproportionately-powerful set of interneurons, in addition to layer 5 and 6 pyramidal neurons. In subjects with functionally-unaltered CHRNA5, the proportion of chandelier cells in the prefrontal cortex shows resilience to β-amyloid load, but this resilience is diminished in subjects homozygous for the minor allele of the CHRNA5 missense SNP rs16969968. Taken together, these findings urge further investigation into the role of CHRNA5 and chandelier cells in AD neuroprotection.

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Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Cited by 289 publications

References 81 publications

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy

Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy

Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

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