James A. R. Nicoll

University of Southampton, Southampton, England, United Kingdom

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Publications (171)993.89 Total impact

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    ABSTRACT: Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 08/2015; DOI:10.1016/j.bbadis.2015.08.024 · 4.66 Impact Factor
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    Jurgita Zekonyte · Kenji Sakai · James A.R. Nicoll · Roy O. Weller · Roxana O. Carare ·
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    ABSTRACT: Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer's disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. The motive force for the elimination of Aβ along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, Aβ rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E ε4 (ApoE4) mice. For drainage of Aβ to occur in a direction contrary to the pulse wave some form of attachment to basement membrane would be required to prevent reflux of Aβ back into the brain during the passage of the subsequent pulse wave. In this study, we show first that apolipoprotein E co-localizes with Aβ in basement membrane drainage pathways in the walls of arteries. Secondly, we show by Atomic Force Microscopy that attachment of ApoE4/Aβ complexes to basement membrane laminin is significantly weaker than ApoE3/Aβ complexes. These results suggest that perivascular elimination of ApoE4/Aβ complexes would be less efficient than with other isoforms of apolipoprotein E, thus endowing a higher risk for Alzheimer's disease. Therapeutic correction for ApoE4/Aβ/laminin interactions may increase the efficiency of elimination of Aβ in the prevention of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 08/2015; DOI:10.1016/j.bbadis.2015.08.025 · 4.88 Impact Factor
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    ABSTRACT: We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled "hereditary diffuse leukencephalopathy with axonal spheroids" (HDLS) and "pigmentary orthochromatic leukodystrophy" (POLD), disorders which now appear to form a disease continuum. The term "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.
    Scientific Reports 05/2015; 5:10042. DOI:10.1038/srep10042 · 5.58 Impact Factor
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    Andreas Charidimou · James A. R. Nicoll · Mark O. McCarron ·

    Frontiers in Neurology 05/2015; 6. DOI:10.3389/fneur.2015.00099
  • A Durnford · J Dunbar · J Galea · D Bulters · J A R Nicoll · D Boche · I Galea ·
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    ABSTRACT: Rapid and effective clearance of cell-free haemoglobin after subarachnoid haemorrhage (SAH) is important to prevent vasospasm and neurotoxicity and improve long-term outcome. Haemoglobin is avidly bound by haptoglobin, and the complex is cleared by CD163 expressed on the membrane surface of macrophages. We studied the kinetics of haemoglobin and haptoglobin in cerebrospinal fluid after SAH. We show that haemoglobin levels rise gradually after SAH. Haptoglobin levels rise acutely with aneurysmal rupture as a result of injection of blood into the subarachnoid space. Although levels decline as haemoglobin scavenging occurs, complete depletion of haptoglobin does not occur and levels start rising again, indicating saturation of CD163 sites available for haptoglobin-haemoglobin clearance. In a preliminary neuropathological study we demonstrate that meningeal CD163 expression is upregulated after SAH, in keeping with a proinflammatory state. However, loss of CD163 occurs in meningeal areas with overlying blood compared with areas without overlying blood. Becauses ADAM17 is the enzyme responsible for shedding membrane-bound CD163, its inhibition may be a potential therapeutic strategy after SAH.
    Acta neurochirurgica. Supplement 01/2015; 120:51-4. DOI:10.1007/978-3-319-04981-6_9
  • L. De Picker · M. Morrens · B.G.C. Sabbe · S. Gentleman · J.A.R. Nicoll · D. Boche ·

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    Cheryl A. Hawkes · Steve M. Gentleman · James A.R. Nicoll · Roxana O. Carare ·
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    ABSTRACT: Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides in the extracellular spaces of the brain as plaques and in the walls of blood vessels as cerebral amyloid angiopathy (CAA). Failure of perivascular drainage of Aβ along cerebrovascular basement membranes contributes to the development of CAA. Mid-life hypercholesterolemia is a risk factor for the development of AD. Maternal obesity is associated with the development of obesity, hypertension and hypercholesterolemia in adulthood, suggesting that the risk for AD and CAA may also be influenced by early life environment. In the present study, we tested the hypothesis that early life exposure to a high fat diet results in changes to the cerebrovasculature and failure of Aβ clearance from the brain. We also assessed if vascular Aβ deposition is greater in the brains of aged humans with a history of hyperlipidemia, compared to age-matched controls with normal lipidemia. Using a mouse model of maternal obesity, we found that exposure to a high fat diet during gestation and lactation induced changes in multiple components of the neurovascular unit, including a downregulation in collagen IV, fibronectin and apolipoprotein E, an upregulation in markers of astrocytes and perivascular macrophages and altered blood vessel morphology in the brains of adult mice. Sustained high fat diet over the entire lifespan resulted in additional decreases in levels of pericytes and impaired perivascular clearance of Aβ from the brain. In humans, vascular Aβ load was significantly increased in the brains of aged individuals with a history of hypercholesterolemia. These results support a critical role for early dietary influence on the brain vasculature across the lifespan, with consequences for the development of age-related cerebrovascular and neurodegenerative diseases.
    The Journal of Pathology 10/2014; 235(4). DOI:10.1002/path.4468 · 7.43 Impact Factor
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    ABSTRACT: Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form of primary brain tumour, with recent emerging evidence that these cell types may interact in glioma models. It is unclear whether microglia and stem cells are associated in human gliomas. To investigate this question, we used the technique of tissue microarrays to perform a correlative study of a large number of tumour samples. We quantified immunostaining of human astrocytic tumour tissue microarrays (86 patients; WHO grade II-IV) for microglia Iba1 and CD68, and stem cell nestin, SOX2 and CD133. Ki67 was used to assess proliferation and GFAP for astrocytic differentiation. Immunoreactivity for both microglial markers and stem cell markers nestin and SOX2 significantly increased with increasing tumour grade. GFAP was higher in low grade astrocytomas. There was a positive correlation between: (i) both microglial markers and nestin and CD133, (ii) nestin and tumour cell proliferation Ki67 and (iii) both microglial markers and Ki67. SOX2 was not associated with microglia or tumour proliferation. To test the clinical relevance, we investigated the putative association of these markers with clinical outcomes. High expression for nestin and Iba1 correlated with significantly shorter survival times, and high expression for nestin, Iba1, CD68 and Ki67 was associated with faster tumour progression on univariate analysis. On multivariate analysis, nestin, CD133 and Ki67 remained significant predictors of poorer survival, after adjustment for other markers. These results confirm previous in vitro findings, demonstrating their functional relevance as a therapeutic target in humans. This is the first report of a novel correlation between microglia and stem cells that may drive human astrocytic tumour development.
    10/2014; 1(2). DOI:10.1002/cjp2.7
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    ABSTRACT: Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes.
    Acta Neuropathologica 09/2014; 128(6). DOI:10.1007/s00401-014-1340-9 · 10.76 Impact Factor

  • Neuropathology and Applied Neurobiology 03/2014; 40:46-47. · 3.93 Impact Factor

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    ABSTRACT: Objective Traumatic brain injury (TBI) is a multifactorial pathology with great interindividual variability in response to injury and outcome. Mitochondria contain their own DNA (mtDNA) with genomic variants that have different physiological and pathological characteristics, including susceptibility to neurodegeneration. Given the central role of mitochondria in the pathophysiology of neurological injury, we hypothesized that its genomic variants may account for the variability in outcome following TBI. Methods We undertook an analysis of mitochondrial haplogroups in a large, well‐characterized cohort of 1,094 TBI patients. A proportional odds model including age, brain computed tomography characteristics, injury severity, pupillary reactivity, mitochondrial haplogroups, and APOE was applied to Glasgow Outcome Score (GOS) data. Results mtDNA had a significant association with 6‐month GOS (p = 0.008). Haplogroup K was significantly associated with favorable outcome (odds ratio = 1.64, 95% confidence interval = 1.08–2.51, p = 0.02). There was also a significant interaction between mitochondrial genome and age (p = 0.002), with a strong protective effect of both haplogroups T (p = 0.015) and K (p = 0.017) with advancing age. We also found a strong interaction between APOE and mitochondrial haplogroups (p = 0.001), indicating a protective effect of haplogroup K in carriers of the APOE ε4 allele. Interpretation These findings reveal an interplay between mitochondrial DNA, pathophysiology of TBI, and aging. Haplogroups K and T, which share a common maternal ancestor, are shown as protective in TBI. The data also suggest that the APOE pathways interact with genetically regulated mitochondrial functions in the response to acute injury, as previously reported in Alzheimer disease. Ann Neurol 2014;75:186–195
    Annals of Neurology 02/2014; 75(2). DOI:10.1002/ana.24116 · 9.98 Impact Factor
  • Carole J Proctor · Delphine Boche · Douglas A Gray · James A R Nicoll ·
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    ABSTRACT: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.
    PLoS ONE 09/2013; 8(9):e73631. DOI:10.1371/journal.pone.0073631 · 3.23 Impact Factor
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    ABSTRACT: Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-β42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.
    Brain 08/2013; 136(9). DOI:10.1093/brain/awt210 · 9.20 Impact Factor
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    ABSTRACT: Clinical outcome after traumatic brain injury (TBI) is variable and cannot easily be predicted. There is increasing evidence to suggest there may be genetic influences on outcome. Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6-months after head injury. A prospectively identified cohort of patients (n=1096, age range 0-93, mean age 37) was utilised. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome (TNFA -238 and -308, IL6 -174, -572 and -597, IL1A -889, IL1B -31, -511 and +3953 and TGFB -509 and -800) TNFA -308 was identified as having a likely association. The TNFA -308 SNP was further evaluated and a significant association was identified, with 39% of allele 2 carriers having an unfavourable outcome compared with 31% of non-carriers (adjusted OR 1.67, CI 1.19-2.35, p=0.003). These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that TNFα plays an important role in this process.
    Journal of neurotrauma 06/2013; 30(20). DOI:10.1089/neu.2012.2792 · 3.71 Impact Factor
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    D Boche · J A R Nicoll ·

    Neuropathology and Applied Neurobiology 02/2013; 39(1):1-2. DOI:10.1111/nan.12009 · 3.93 Impact Factor
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    ABSTRACT: Aims: Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long-term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimer's disease, and it has been hypothesized that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury. Methods: This study assessed the microglial reaction after head injury in a range of ages and survival periods, from <24-h survival through to 47-year survival. Immunohistochemistry for reactive microglia (CD68 and CR3/43) was performed on human autopsy brain tissue and assessed 'blind' by quantitative image analysis. Head injury cases were compared with age matched controls, and within the traumatic brain injury group cases with diffuse traumatic axonal injury were compared with cases without diffuse traumatic axonal injury. Results: A major finding was a neuroinflammatory response that develops within the first week and persists for several months after traumatic brain injury, but has returned to control levels after several years. In cases with diffuse traumatic axonal injury the microglial reaction is particularly pronounced in the white matter. Conclusions: These results demonstrate that prolonged microglial activation is a feature of traumatic brain injury, but that the neuroinflammatory response returns to control levels after several years.
    Neuropathology and Applied Neurobiology 12/2012; 39(6). DOI:10.1111/nan.12008 · 3.93 Impact Factor
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    ABSTRACT: Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.
    PLoS ONE 07/2012; 7(7):e41636. DOI:10.1371/journal.pone.0041636 · 3.23 Impact Factor
  • C Billingham · M R Powell · K A Jenner · D A Johnston · M Gatherer · J A R Nicoll · D Boche ·
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    ABSTRACT: Aim: Microglia form a high proportion of cells in glial tumours but their role in supporting or inhibiting tumour growth is unclear. Here we describe the establishment of an in vitro model to investigate their role in astrocytomas. Methods: Rat hippocampal slices were prepared and, after 7 days to allow microglia to become quiescent, rat C6 astrocytic tumour cells were added. Over the following 7 days, infiltration and cell death were studied using fluorescent C6 tumour cells and confocal microscopy; immunophenotyping of microglia was performed using CD68 (phagocytosis), MHCII (antigen-presentation) and Iba1 (microglial marker regardless of functional state). Cell proliferation was assessed using Ki67 and qPCR to detect cytokine expression. Sham and control groups were included. Results: Microscopy showed proliferation of C6 tumour cells with both infiltration of tumour cells into the hippocampal tissue and of microglia among the tumour cells. Confocal experiments confirmed increasing tumour cell infiltration into the hippocampal slice with time (P<0.001), associated with cell death (σ=0.313, P=0.022). Ki67 showed increased proliferation (P<0.001), of both tumour cells and Iba1+ microglia and increased microglial phagocytosis (CD68: P<0.001). Expression of pro-inflammatory cytokines IL1, IL6 and TNFα were downregulated with expression of the anti-inflammatory cytokine TGFβ1 maintained. Conclusion: This model allows study of the proliferation and infiltration of astrocytic tumour cells in central nervous system tissue and their interaction with microglia. Our data suggest that microglial function is altered in the presence of tumour cells, putatively facilitating tumour progression. Manipulation of the microglial functional state may have therapeutic value for astrocytic tumours. © 2012 The Authors. Neuropathology and Applied Neurobiology
    Neuropathology and Applied Neurobiology 05/2012; 39(3). DOI:10.1111/j.1365-2990.2012.01283.x · 3.93 Impact Factor
  • Roy O. Weller MD, PhD, FRCPath · Seth Love · James A. R. Nicoll ·
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    ABSTRACT: The brain is the only organ in which there is a significant problem with elimination of amyloid β with age, and substantial accumulation of amyloid β in Alzheimer's disease. Here we examine the pathways by which amyloid β is eliminated from the brain and the reasons why elimination fails with age. Lymphatic drainage of interstitial fluid and solutes, such as amyloid β, appears to be along the basement membranes of cerebral capillaries and arteries to cervical lymph nodes. Enzymes, such as neprilysin, that degrade amyloid β, and mechanisms for absorption of amyloid β into the blood are distributed along the lymphatic drainage pathways but they fail with age. As arteries themselves age, transport of amyloid β along perivascular drainage pathways also fails and results in cerebral amyloid angiopathy. We review the results of immunotherapy designed to clear amyloid β from the brain, and we suggest that a clear understanding of how amyloid β is eliminated may result in more effective therapies for Alzheimer's disease.
    Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, Second Edition, 09/2011: pages 97 - 101; , ISBN: 9781444341256

Publication Stats

9k Citations
993.89 Total Impact Points


  • 2002-2015
    • University of Southampton
      • • Faculty of Medicine
      • • Clinical Neurosciences
      Southampton, England, United Kingdom
    • Imperial College London
      • Faculty of Medicine
      Londinium, England, United Kingdom
  • 2012-2014
    • University Hospital Southampton NHS Foundation Trust
      • Wessex Neurological Centre
      Southampton, England, United Kingdom
  • 2003-2006
    • The University of Edinburgh
      • Division of Pathology
      Edinburgh, Scotland, United Kingdom
    • King's College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
  • 1996-2003
    • University of Glasgow
      • Division of Anatomy
      Glasgow, Scotland, United Kingdom
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1991-1993
    • Bristol Hospital
      Bristol, Connecticut, United States
  • 1992
    • University of Bristol
      • School of Clinical Sciences
      Bristol, England, United Kingdom