PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice

Review Neurosciences

Brain cell type-specific cholesterol metabolism and implications for learning and memory

Dingfeng Li et al.

Summary: Cholesterol homeostasis plays a vital role in brain function, with locally synthesized cholesterol and its transfer between different cell types having implications for brain aging and Alzheimer's disease.

TRENDS IN NEUROSCIENCES (2022)

Add to Collection

Review Pathology

Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms

Nicole Koutsodendris et al.

Summary: Alzheimer's disease (AD) is a complex neurodegenerative disorder that is difficult to treat. Recent advancements in imaging technology and experimental techniques have allowed researchers to gain insights into the pathogenic mechanisms of AD. The major genetic risk factor for late-onset AD, apolipoprotein E4 (apoE4), plays a significant role in the initiation and progression of AD, although its exact mechanisms are not fully understood.

ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE (2022)

Add to Collection

Article Biochemistry & Molecular Biology

PCSK9 acts as a key regulator of Aβ clearance across the blood-brain barrier

Alexander D. Mazura et al.

Summary: Despite the lack of available therapies for Alzheimer's disease, research has found that reducing circulating PCSK9 levels can improve the clearance of cerebral amyloid-beta and reduce the burden of disease-related pathology in the brain, as well as improve memory processing.

CELLULAR AND MOLECULAR LIFE SCIENCES (2022)

Add to Collection

Article Genetics & Heredity

New insights into the genetic etiology of Alzheimer's disease and related dementias

Celine Bellenguez et al.

Summary: By characterizing the genetic landscape of Alzheimer's disease and related dementias, new loci have been identified and a new genetic risk score associated with the risk of future Alzheimer's disease and dementia has been generated.

NATURE GENETICS (2022)

Add to Collection

Article Biochemistry & Molecular Biology

Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release

Rafael Jaen et al.

Summary: Atherosclerosis is a cardiovascular disease characterized by the formation of plaques and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important protein involved in atherosclerosis. Through LDLR, human macrophages can take up circulating PCSK9, which activates the TLR4 pathway and leads to increased reactive oxygen species production, reduced lipid metabolism and cholesterol efflux gene expression, and enhanced pro-inflammatory cytokine production. This ultimately compromises macrophage viability and contributes to the progression of atherosclerosis.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Add to Collection

Review Biochemistry & Molecular Biology

Therapeutics of Alzheimer's Disease: Recent Developments

Scott Burns et al.

Summary: Dementia, particularly Alzheimer's disease, is a growing public health concern globally due to aging populations. Significant progress has been made in understanding the biology and progression of Alzheimer's disease in the last three decades, leading to the development of therapeutic strategies, though challenges remain. New strategies are needed to combat this devastating mental illness.

ANTIOXIDANTS (2022)

Add to Collection

Review Biochemistry & Molecular Biology

Staging of Alzheimer?s disease: past, present and future perspectives

Joseph Therriault et al.

Summary: For many years, Alzheimer's disease has been primarily associated with dementia, but recent studies have shown that AD patients go through a long preclinical phase before cognitive decline, which can be staged using imaging and biomarkers.

TRENDS IN MOLECULAR MEDICINE (2022)

Add to Collection

Article Biochemistry & Molecular Biology

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer's Disease

Bianca Papotti et al.

Summary: The involvement of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Alzheimer's disease (AD) has been poorly investigated. This study found that PCSK9 can interfere with cholesterol metabolism between astrocytes and neurons, leading to a reduction in neuronal cholesterol and potentially harmful effects. Additionally, PCSK9 exhibited neurotoxicity. These findings suggest that PCSK9 could be a potential pharmacological target in the treatment of AD.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Add to Collection

Article Cardiac & Cardiovascular Systems

PCSK9 and LRP5 in macrophage lipid internalization and inflammation

Lina Badimon et al.

Summary: The study demonstrates that LRP5 plays a crucial role in macrophage lipid uptake, and in the absence of both LRP5 and PCSK9, there is a significant reduction in CE accumulation, indicating a role for both proteins in lipid uptake. Additionally, LRP5 forms a complex with PCSK9 in lipid-loaded macrophages.

CARDIOVASCULAR RESEARCH (2021)

Add to Collection

Article Multidisciplinary Sciences

Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer's disease transgenic mouse model

Jackie K. Y. Lau et al.

Summary: The study demonstrates that MCR activation significantly reduces A beta accumulation and alleviates inflammation and astrocytic activation in the hippocampus of APP/PS1 transgenic mice, suggesting the potential therapeutic target for Alzheimer's disease.

SCIENTIFIC REPORTS (2021)

Add to Collection

Article Multidisciplinary Sciences

Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer's disease

Stefania Forner et al.

Summary: Mouse models of human diseases are crucial for studying pathogenic mechanisms and testing interventions. To effectively evaluate new therapeutic approaches, it is important to identify the most appropriate model and age. In this study, a detailed phenotypic characterization of the 5xFAD model was conducted to provide insights into age-related pathology.

SCIENTIFIC DATA (2021)

Add to Collection

Review Neurosciences

The role of pathological tau in synaptic dysfunction in Alzheimer's diseases

Moxin Wu et al.

Summary: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, with synaptic dysfunction recognized as the main cause of cognitive impairments. Pathological tau is suggested to induce synaptic dysfunction in various ways, contributing to cognitive decline in AD. Exploring the mechanism by which pathological tau impairs synaptic function is crucial for developing novel therapeutic strategies for AD.

TRANSLATIONAL NEURODEGENERATION (2021)

Add to Collection

Article Medicine, Research & Experimental

HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis

Sally A. Abuelezz et al.

Summary: Inhibition of PCSK9 by Alirocumab shows promise in ameliorating cognitive deficits, cholesterol homeostasis, and neuro-inflammation in HFCD-induced AD-like condition.

LIFE SCIENCES (2021)

Add to Collection

Article Chemistry, Medicinal

Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease

Massimiliano Runfola et al.

Summary: In order to treat Alzheimer's disease, researchers designed a compound called SG2 with pleiotropic effects such as promoting autophagic flux, neuroprotection, and metabolic reprogramming. In animal model experiments, SG2 showed the ability to promote recovery in the AD model and improve learning abilities. This compound has been confirmed to have low toxicity, serving as a potential starting point for the development of AD drugs.

PHARMACEUTICALS (2021)

Add to Collection

Article Neurosciences

A regional and cellular analysis of the early intracellular and extracellular accumulation of Aβ in the brain of 5XFAD mice

Eleonora Daini et al.

Summary: This study investigated the early development of A beta pathology in 5XFAD mice, a severe transgenic mouse model of AD, and found that A beta pathology develops in many brain regions, with iA beta being transient and followed by eA beta in grey matter regions. The activation of microglia is associated with early iA beta, while the subsequent formation of eA beta plaques is associated with increased density of microglial cells.

NEUROSCIENCE LETTERS (2021)

Add to Collection

Article Geriatrics & Gerontology

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

Adrian L. Oblak et al.

Summary: The development of AD animal models depends on comprehensive characterization, current models have limitations and cannot fully recapitulate the full effects of AD in humans, hence the MODEL-AD consortium was formed by NIA to develop more relevant and clinically useful AD animal models.

FRONTIERS IN AGING NEUROSCIENCE (2021)

Add to Collection

Review Geriatrics & Gerontology

Cholesterol and Alzheimer's Disease; From Risk Genes to Pathological Effects

Femke M. Feringa et al.

Summary: The brain tightly regulates cholesterol levels for physiological function, but excessive accumulation may contribute to Alzheimer's disease. Genetic risk factors associated with cholesterol metabolism may impact AD pathology. Advances in CRISPR/Cas9 gene editing and iPSC technology hold promise for further understanding these mechanisms.

FRONTIERS IN AGING NEUROSCIENCE (2021)

Add to Collection

Article Clinical Neurology

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease

Maya Koronyo-Hamaoui et al.

BRAIN (2020)

Add to Collection

Article Biochemistry & Molecular Biology

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor exerts greater efficacy than atorvastatin on improvement of brain function and cognition in obese rats

Busarin Arunsak et al.

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS (2020)

Add to Collection

Review Immunology

The Role of Astrocytes in CNS Inflammation

Federico Giovannoni et al.

TRENDS IN IMMUNOLOGY (2020)

Add to Collection

Article Biochemistry & Molecular Biology

A quantitative LC-MS/MS method for analysis of mitochondrial-specific oxysterol metabolism

Khushboo Borah et al.

REDOX BIOLOGY (2020)

Add to Collection

Review Neurosciences

A Unifying Hypothesis for Alzheimer's Disease: From Plaques to Neurodegeneration

Frances A. Edwards

TRENDS IN NEUROSCIENCES (2019)

Add to Collection

Review Geriatrics & Gerontology

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer's Disease

Maria Pia Adorni et al.

FRONTIERS IN AGING NEUROSCIENCE (2019)

Add to Collection

Article Multidisciplinary Sciences

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study

Cynthia Picard et al.

PLOS ONE (2019)

Add to Collection

Article Cardiac & Cardiovascular Systems

Pretreatment With PCSK9 Inhibitor Protects the Brain Against Cardiac lschemia/Reperfusion Injury Through a Reduction of Neuronal Inflammation and Amyloid Beta Aggregation

Nattayaporn Apaijai et al.

JOURNAL OF THE AMERICAN HEART ASSOCIATION (2019)

Add to Collection

Article Neurosciences

PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease

Helene Courtemanche et al.

JOURNAL OF ALZHEIMERS DISEASE (2018)

Add to Collection

Article Geriatrics & Gerontology

Loss-of-Function PCSK9 Mutations Are Not Associated With Alzheimer Disease

Martine Paquette et al.

JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY (2018)

Add to Collection

Article Medicine, General & Internal

PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque

A. Liu et al.

JOURNAL OF INTERNAL MEDICINE (2018)

Add to Collection

Article Multidisciplinary Sciences

PCSK9 induces a pro-inflammatory response in macrophages

Chiara Ricci et al.

SCIENTIFIC REPORTS (2018)

Add to Collection

Article Immunology

LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response

Giovanna Rigillo et al.

BRAIN BEHAVIOR AND IMMUNITY (2018)

Add to Collection

Article Neurosciences

Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease

Francesca Zimetti et al.

JOURNAL OF ALZHEIMERS DISEASE (2017)

Add to Collection

Article Neurosciences

PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway

Lu-Shan Liu et al.

JOURNAL OF ALZHEIMERS DISEASE (2017)

Add to Collection

Article Cardiac & Cardiovascular Systems

New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway

Zhi-Han Tang et al.

ATHEROSCLEROSIS (2017)

Add to Collection

Article Clinical Neurology

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease

Katherine R. Sadleir et al.

ACTA NEUROPATHOLOGICA (2016)

Add to Collection

Article Hematology

Central Nervous System Lipoproteins ApoE and Regulation of Cholesterol Metabolism

Robert W. Mahley

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (2016)

Add to Collection

Article Clinical Neurology

Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer's disease

Yosef Koronyo et al.

BRAIN (2015)

Add to Collection

Article Immunology

Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10

Beatriz Almolda et al.

BRAIN BEHAVIOR AND IMMUNITY (2015)

Add to Collection

Article Neurosciences

Astrocyte-Targeted Production of IL-10 Induces Changes in Microglial Reactivity and Reduces Motor Neuron Death After Facial Nerve Axotomy

Nadia Villacampa et al.

GLIA (2015)

Add to Collection

Review Immunology

Regulation of inflammasome activation

Si Ming Man et al.

IMMUNOLOGICAL REVIEWS (2015)

Add to Collection

Article Clinical Neurology

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

Clifford R. Jack et al.

LANCET NEUROLOGY (2013)

Add to Collection

Review Clinical Neurology

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

Chia-Chan Liu et al.

NATURE REVIEWS NEUROLOGY (2013)

Add to Collection

Article Neurosciences

Microglial Beclin 1 Regulates Retromer Trafficking and Phagocytosis and Is Impaired in Alzheimer's Disease

Kurt M. Lucin et al.

NEURON (2013)

Add to Collection

Article Biochemistry & Molecular Biology

PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

Kai Kysenius et al.

CELLULAR AND MOLECULAR LIFE SCIENCES (2012)

Add to Collection

Article Genetics & Heredity

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Paul Hollingworth et al.

NATURE GENETICS (2011)

Add to Collection

Article Biochemistry & Molecular Biology

PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain

Mali Liu et al.

JOURNAL OF LIPID RESEARCH (2010)

Add to Collection

Article Multidisciplinary Sciences

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Lesley Jones et al.

PLOS ONE (2010)

Add to Collection

Article Biochemistry & Molecular Biology

The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2

Steve Poirier et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2008)

Add to Collection

Article Neurosciences

BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice

Masuo Ohno et al.

NEUROBIOLOGY OF DISEASE (2007)

Add to Collection

Article Biochemical Research Methods

Proapoptotic effects of NARC 1 (=PCSK9), the gene encoding a novel serine proteinase

Brendan Bingham et al.

CYTOMETRY PART A (2006)

Add to Collection

Article Biochemical Research Methods

Morris water maze: procedures for assessing spatial and related forms of learning and memory

Charles V. Vorhees et al.

NATURE PROTOCOLS (2006)

Add to Collection

Article Multidisciplinary Sciences

The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1):: Liver regeneration and neuronal differentiation

NG Seidah et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2003)

Add to Collection

Review Biochemistry & Molecular Biology

Cholesterol metabolism in the brain

JM Dietschy et al.

CURRENT OPINION IN LIPIDOLOGY (2001)

Add to Collection

PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice

Related references

Export Citation

Share Paper