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Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

ABSTRACT: The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

SUBMITTER: Zhou LT

PROVIDER: S-EPMC10121173 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

Zhou Lan-Ting LT Liu Dan D Kang Hui-Cong HC Lu Lu L Huang He-Zhou HZ Ai Wen-Qing WQ Zhou Yang Y Deng Man-Fei MF Li Hao H Liu Zhi-Qiang ZQ Zhang Wei-Feng WF Hu Ya-Zhuo YZ Han Zhi-Tao ZT Zhang Hong-Hong HH Jia Jian-Jun JJ Sarkar Avijite Kumer AK Sharaydeh Saldin S Wang Jie J Man Heng-Ye HY Schilling Marcel M Bertram Lars L Lu Youming Y Guo Ziyuan Z Zhu Ling-Qiang LQ

Science advances 20230421 16

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived n ...[more]

PMID: 37083538

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Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

Project description:BackgroundEarly Alzheimer's disease diagnosis is crucial for preventive therapy development. Standard neuropsychological evaluation does not identify clinically normal individuals with brain amyloidosis, the first stage of the pathology, defined as preclinical Alzheimer's disease. Spatial navigation assessment, in particular path integration, appears promising to detect preclinical symptoms, as the medial temporal lobe plays a key role in navigation and is the first cortical region affected by tau pathology.MethodsWe have conducted a cross-sectional study. We related the path integration performance of 102 individuals without dementia, aged over 50, to amyloid and tau pathologies, measured using positron emission tomography. We included 75 clinically normal individuals (19 with brain amyloidosis, 56 without) and 27 individuals with mild cognitive impairment (18 with brain amyloidosis, 9 without). We fitted linear mixed models to predict the path integration performances according to amyloid status or tau pathology in the medial temporal lobal, adjusting for age, gender, cognitive status, education, and video game experience. We decomposed the error into rotation and distance errors.ResultsWe observed that clinically normal adults with brain amyloidosis (preclinical Alzheimer's disease) had spatial navigation deficits when relying only on self-motion cues. However, they were able to use a landmark to reduce their errors. Individuals with mild cognitive impairment had deficits in path integration that did not improve when a landmark was added in the environment. The amyloid status did not influence performance among individuals with mild cognitive impairment. Among all individuals, rotation, but not distance, errors increased with the level of tau pathology in the medial temporal lobe.ConclusionOur results suggest that path integration performance in an environment without external cues allows identifying individuals with preclinical Alzheimer's disease, before overt episodic memory impairment is noticeable. Specifically, we demonstrated that poor angular estimation is an early cognitive marker of tau pathology, whereas distance estimation relates to older ages, not to Alzheimer's disease.Trial registrationEudra-CT 2018-003473-94.

Project description:BackgroundIn Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).MethodsWe included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.ResultsRegarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073--0.069, pFDR 0.001-0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099--0.063, pFDR < 0.001-0.046), synaptic (14-3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal.ConclusionsBiomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.

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Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

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Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

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