Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate

AbstractAmyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer’s disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.

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Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice

American Journal Of Pathology ◽

10.2353/ajpath.2007.070403 ◽

2007 ◽

Vol 171 (6) ◽

pp. 2012-2020 ◽

Cited By ~ 168

Author(s):

Tristan Bolmont ◽

Florence Clavaguera ◽

Melanie Meyer-Luehmann ◽

Martin C. Herzig ◽

Rebecca Radde ◽

...

Keyword(s):

Transgenic Mice ◽

Amyloid Β ◽

Brain Extract ◽

Tau Pathology ◽

Intracerebral Infusion

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Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00761-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Yanxing Chen ◽

Shuai Zhao ◽

Ziqi Fan ◽

Zheyu Li ◽

Yueli Zhu ◽

...

Keyword(s):

Amyloid Β ◽

Tau Proteins ◽

Dystrophic Neurites ◽

Wild Type ◽

Tau Pathology ◽

Immunofluorescence Analysis ◽

Reciprocal Interactions ◽

Brain Extracts ◽

Amyloid Cascade ◽

Positive Effect

Abstract Background The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. Methods Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. Results We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. Conclusion These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

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Induction of amyloid-β deposits from serially transmitted, histologically silent, Aβ seeds issued from human brains

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01081-7 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Anne-Sophie Hérard ◽

◽

Fanny Petit ◽

Charlotte Gary ◽

Martine Guillermier ◽

...

Keyword(s):

Mouse Models ◽

Amyloid Β ◽

Brain Homogenate ◽

Amyloid Deposit ◽

Positive Sample ◽

Precursor Protein ◽

Post Inoculation ◽

Brain Extracts ◽

Iatrogenic Transmission ◽

High Level

AbstractIn humans, iatrogenic transmission of cerebral amyloid-β (Aβ)-amyloidosis is suspected following inoculation of pituitary-derived hormones or dural grafts presumably contaminated with Aβ proteins as well as after cerebral surgeries. Experimentally, intracerebral inoculation of brain homogenate extracts containing misfolded Aβ can seed Aβ deposition in transgenic mouse models of amyloidosis or in non-human primates. The transmission of cerebral Aβ is governed by the host and by the inoculated samples. It is critical to better characterize the propensities of different hosts to develop Aβ deposition after contamination by an Aβ-positive sample as well as to better assess which biological samples can transmit this lesion. Aβ precursor protein (huAPPwt) mice express humanized non-mutated forms of Aβ precursor protein and do not spontaneously develop Aβ or amyloid deposits. We found that inoculation of Aβ-positive brain extracts from Alzheimer patients in these mice leads to a sparse Aβ deposition close to the alveus 18 months post-inoculation. However, it does not induce cortical or hippocampal Aβ deposition. Secondary inoculation of apparently amyloid deposit-free hippocampal extracts from these huAPPwt mice to APPswe/PS1dE9 mouse models of amyloidosis enhanced Aβ deposition in the alveus 9 months post-inoculation. This suggests that Aβ seeds issued from human brain samples can persist in furtive forms in brain tissues while maintaining their ability to foster Aβ deposition in receptive hosts that overexpress endogenous Aβ. This work emphasizes the need for high-level preventive measures, especially in the context of neurosurgery, to prevent the risk of iatrogenic transmission of Aβ lesions from samples with sparse amyloid markers.

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microRNA-150-5p: A Novel Blood-Based Biomarker for Alzheimer’s Dementia with Good Correlation to Cognition, Cerebrospinal Fluid Amyloid-β, and Cerebral Atrophy

10.21203/rs.3.rs-942370/v1 ◽

2021 ◽

Author(s):

Sook-Yoong Chia ◽

Ashwati Vipin ◽

Kok-Pin Ng ◽

Haitao Tu ◽

Ananth Bommakanti ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medial Temporal Lobe ◽

Target Genes ◽

Mononuclear Cells ◽

Amyloid Β ◽

Cerebral Atrophy ◽

Posterior Cingulate Cortex ◽

Peripheral Blood Mononuclear ◽

Clinical Measures

Abstract Background: There is an urgent need for non-invasive, cost-effective biomarkers for Alzheimer’s disease (AD), such as blood-based biomarkers. It is not only to support clinical diagnosis of dementia, but also to allow for timely pharmacological and non-pharmacological interventions evaluation. The aim of this study is to identify and validate a novel blood-based microRNA (miRNA) biomarker for dementia of Alzheimer’s disease type (DAT). The miRNA correlations with AD pathology and AD clinical-radiological imaging were conducted.Methods: We conducted miRNA-sequencing (miRNA-Seq) using peripheral blood mononuclear cells (PBMCs) isolated from a discovery cohort comprising DAT, mild cognitive impairment (MCI), and healthy subject (HS). Identified miRNA was validated in an independent cohort. Correlation analysis evaluated the relationships between miRNA expression and DAT clinical measures, including Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, CSF Aβ1-42 and tau levels, and AD pattern cerebral atrophy. Furthermore, we conducted bioinformatics analysis and cell-based assay to identify miRNA target genes. Results: MiRNA-seq identified a distinct miRNA (miR-328-3p, miR-7706, and miR-150-5p) expression signature differentiating DAT from MCI and HS. qPCR analysis reveals that miR-150-5p was consistent with the miRNA-seq data and was further validated. Specifically, we found that miR-150-5p expression was significantly upregulated in DAT compared to MCI and HS, and discriminated DAT from MCI and HS with a high accuracy with AUC of 0.86 and 0.86, respectively. We further found that higher miR-150-5p levels correlated with clinical measures of DAT, including lower global cognitive scores of MMSE and MoCA, lower CSF Aβ1-42, and higher CSF tau. Interestingly, we observed that higher miR-150-5p levels is associated with the lower grey matter volumes in the medial temporal lobe, posterior cingulate cortex and precuneus. These regions implicated default mood network and executive control network regions that are important for AD brain atrophy. Furthermore, pathway analysis identified the targets of miR-150-5p to be enriched in the Wnt signalling pathway, including programmed cell death 4 (PDCD4). We further found that PDCD4 was downregulated in DAT blood and was downregulated by miR-150-5p at both transcriptional and protein levels.Conclusions: Our findings demonstrated that miR-150-5p is a reliable clinical blood-based biomarker for DAT.

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Exogenous Aβ seeds induce Aβ depositions in the blood vessels rather than the brain parenchyma, independently of Aβ strain-specific information

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01252-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Tsuyoshi Hamaguchi ◽

Jee Hee Kim ◽

Akane Hasegawa ◽

Ritsuko Goto ◽

Kenji Sakai ◽

...

Keyword(s):

Human Brain ◽

Blood Vessels ◽

Brain Homogenate ◽

Brain Parenchyma ◽

Brain Extract ◽

Amyloid Angiopathy ◽

Specific Information ◽

Brain Extracts ◽

Iatrogenic Transmission ◽

The Brain

AbstractLittle is known about the effects of parenchymal or vascular amyloid β peptide (Aβ) deposition in the brain. We hypothesized that Aβ strain-specific information defines whether Aβ deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aβ plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer’s disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aβ. One year after the injection, the pathological and biochemical features of Aβ in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aβ depositions were observed in the mice that were injected with the human brain homogenate from the less Aβ group. The Aβ and CAA seeding activities, which had significant positive correlations with the Aβ oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aβ group than in the other three groups. These results indicate that exogenous Aβ seeds from different Aβ pathologies induced Aβ deposition in the blood vessels rather than the brain parenchyma without being influenced by Aβ strain-specific information, which might be why CAA is a predominant feature of Aβ pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aβ pathology might occur due to contamination of brain tissues from patients with little Aβ pathology, and the development of inactivation methods for Aβ seeding activity to prevent iatrogenic transmission is urgently required.

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Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

Current Alzheimer Research ◽

10.2174/1567205016666190801153751 ◽

2019 ◽

Vol 16 (8) ◽

pp. 710-722 ◽

Cited By ~ 11

Author(s):

Xiao-Ying Sun ◽

Quan-Xiu Dong ◽

Jie Zhu ◽

Xun Sun ◽

Li-Fan Zhang ◽

...

Keyword(s):

Cognitive Deficits ◽

Therapeutic Potential ◽

Amyloid Β ◽

Synaptic Proteins ◽

Morris Water Maze Test ◽

Phosphorylated Tau ◽

Tau Pathology ◽

Maze Test ◽

N2a Cells ◽

Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

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Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10071802 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1802

Author(s):

Enrique Armijo ◽

George Edwards ◽

Andrea Flores ◽

Jorge Vera ◽

Mohammad Shahnawaz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Memory Loss ◽

Amyloid Β ◽

Cerebral Atrophy ◽

Brain Inflammation ◽

Neural Precursors ◽

Model Of Alzheimer’S Disease ◽

Induced Pluripotent

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

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Endo-lysosomal Aβ concentration and pH enable formation of Aβ oligomers that potently induce Tau missorting

10.1101/2020.06.28.175885 ◽

2020 ◽

Author(s):

Marie P. Schützmann ◽

Filip Hasecke ◽

Sarah Bachmann ◽

Mara Zielinski ◽

Sebastian Hänsch ◽

...

Keyword(s):

Amyloid Fibrils ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Tau Pathology ◽

Aβ Oligomers ◽

Lysosomal Ph ◽

Amyloid Fibril Formation ◽

Aβ Amyloid ◽

Key Factor ◽

Lysosomal System

AbstractAmyloid-β peptide (Aβ) forms metastable oligomers >50 kD, termed AβOs or protofibrils, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.

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The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

European Neurology ◽

10.1159/000516774 ◽

2021 ◽

Vol 84 (6) ◽

pp. 472-480

Author(s):

Yulin Luo ◽

Li Tan ◽

Joseph Therriault ◽

Hua Zhang ◽

Ying Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apolipoprotein E ◽

Amyloid Β ◽

Disease Assessment ◽

Tau Pathology ◽

Ε4 Allele ◽

State Examination

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

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