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Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimers disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Aging is a predominant risk factor for several chronic diseases that limit healthspan.sup.1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues.sup.2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases. Aptamer-based proteomic analysis of plasma from healthy individuals aged 18-95 years reveals wave-like patterns of protein expression that are associated with age-related diseases and phenotypic traits., Author(s): Benoit Lehallier [sup.1] [sup.2] [sup.3] , David Gate [sup.1] [sup.2] [sup.3] [sup.4] , Nicholas Schaum [sup.5] , Tibor Nanasi [sup.1] [sup.2] [sup.3] [sup.6] , Song Eun Lee [sup.1] [sup.2] [...]

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes. [ABSTRACT FROM AUTHOR]

Background: P75NTR is a key mediator in the regulation of neuronal plasticity, and modulation of its signaling prevents synaptic dysfunction in Tau.P301S mice, as measured by long‐term potentiation (LTP). Since LTP alters gene expression programs and results in transient post‐translational modifications at synapses, we asked whether tauopathy‐associated alterations in gene co‐expression, in response to stimulation, can be counteracted by p75NTR modulation. Method: LM11A‐31 (C31), a small molecule p75NTR modulator, was orally administered to Wildtype (WT) and Tau.P301S mice for 3 months, at a time when tau pathology was fully developed. RNA sequencing with cell‐type enrichment analysis was performed on unstimulated and stimulated hippocampal slices that underwent theta burst stimulation (TBS) to induce late‐phase LTP and generate activity‐dependent profiles of gene co‐expression networks, using weighted analysis with a soft‐threshold power of 18 to achieve scale‐free topology R2>0.8 and module size 25. Result: The most significantly expressed activity‐dependent transcriptional co‐expression modules related to synaptic function in WT mice, that were down‐regulated in Tau.P301S mice, showed an enrichment for genes in neurons and transcripts selectively expressed in CA1 pyramidal cells. The top significant gene pathways enriched in these modules were glutamatergic synapse, post‐synapse, pre‐synapse, post‐synaptic density, dendritic and neuron spine, with Cacna1h, Gabbr1, Kalrn, Shisa7, and Epha7. All of these were normalized to WT levels with C31 treatment. In addition, significantly up‐regulated co‐expression modules in Tau.P301S relative to WT mice associated with pathways such as complement binding, immune system process, myeloid leukocyte migration and neutrophil chemotaxis were enriched in genes found in microglia, such as Trem2, C1qa, C1qb, C1qc, Tyrobp. Notably, these expression profiles also reverted to WT levels with C31. Further, comparison of mouse and human modules demonstrated that those affected in treated mice have similar up‐ and down‐regulated patterns of expression as those found in human AD. Conclusion: Modulation of p75NTR with C31 normalized tauopathy‐related neuronal and glial transcriptional profiles. These transcriptional alterations are in part concordant with alterations found in human AD‐relevant gene co‐expression networks. [ABSTRACT FROM AUTHOR]

Aging is a prominent risk factor for Alzheimer's disease (AD), but the cellular mechanisms underlying neuronal phenotypes remain elusive. Both accumulation of amyloid plaques and neurofibrillary tangles in the brain 1 and age-linked organelle deficits 2-7 are proposed as causes of AD phenotypes but the relationship between these events is unclear. Here, we address this question using a transdifferentiated neuron (tNeuron) model directly from human dermal fibroblasts. Patient-derived tNeurons retain aging hallmarks and exhibit AD-linked deficits. Quantitative tNeuron proteomic analyses identify aging and AD-linked deficits in proteostasis and organelle homeostasis, particularly affecting endosome-lysosomal components. The proteostasis and lysosomal homeostasis deficits in aged tNeurons are exacerbated in sporadic and familial AD tNeurons, promoting constitutive lysosomal damage and defects in ESCRT-mediated repair. We find deficits in neuronal lysosomal homeostasis lead to inflammatory cytokine secretion, cell death and spontaneous development of Aß and phospho-Tau deposits. These proteotoxic inclusions co-localize with lysosomes and damage markers and resemble inclusions in brain tissue from AD patients and APP-transgenic mice. Supporting the centrality of lysosomal deficits driving AD phenotypes, lysosome-function enhancing compounds reduce AD-associated cytokine secretion and Aβ deposits. We conclude that proteostasis and organelle deficits are upstream initiating factors leading to neuronal aging and AD phenotypes., Competing Interests: Competing interests: R.V., J.L. and T.W.-C. are co-founders of Qinotto Inc.

Introduction: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults., Methods: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes., Results: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau 181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = -2.00, p = 0.005, M7: β = -2.39, p < 0.001)., Discussion: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)