Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease

We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer’s disease (AD). The role of lipoprotein particles is to transport cholesterol fro...

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Autores principales:	Delphine Boche, James AR Nicoll
Formato:	article
Lenguaje:	EN
Publicado:	University of Münster / Open Journals System 2021
Materias:	Lipoprotein particles Extracellular matrix Cholesterol transport Apolipoprotein E Alzheimer’s disease Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/9890ce4721294cc38b8e35d6308bff1a
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spelling	oai:doaj.org-article:9890ce4721294cc38b8e35d6308bff1a2021-11-05T18:30:45ZHypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease10.17879/freeneuropathology-2021-34592699-4445https://doaj.org/article/9890ce4721294cc38b8e35d6308bff1a2021-11-01T00:00:00Zhttps://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/3459https://doaj.org/toc/2699-4445 We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer’s disease (AD). The role of lipoprotein particles is to transport cholesterol from glial cells, where it is synthesised, to neurons, which require cholesterol for synaptic plasticity. The lipoprotein particles have a cholesterol-containing hydrophobic core, in which amyloid-β (Aβ) can be solubilised. The core is surrounded by a hydrophilic surface containing apolipoprotein E (APOE) which, as neurons bear receptors for APOE, determines the destination of the particles. The problem arises because the extracellular space is a narrow cleft, barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. We explain how lipoprotein particles could become trapped in the ageing extracellular matrix and that this primary abnormality results in reduced delivery of cholesterol to neurons leading to impaired synaptic plasticity, crucial for learning and memory. It can also explain extracellular Aβ accumulation, to which a microglial response generates a neurotoxic reaction, and intraneuronal tau aggregation, each of which exacerbate the problem. All these players have been known for many years to be important in Alzheimer’s pathogenesis but a single unifying mechanism to explain how they are linked has been lacking. This proposed mechanism, with entrapment of lipoproteins particles as key to the development of AD, can explain the failure of so many clinical trials and points out new directions to be taken. Delphine BocheJames AR NicollUniversity of Münster / Open Journals SystemarticleLipoprotein particlesExtracellular matrixCholesterol transportApolipoprotein EAlzheimer’s diseaseNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFree Neuropathology, Vol 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lipoprotein particles Extracellular matrix Cholesterol transport Apolipoprotein E Alzheimer’s disease Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Lipoprotein particles Extracellular matrix Cholesterol transport Apolipoprotein E Alzheimer’s disease Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Delphine Boche James AR Nicoll Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
description	We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer’s disease (AD). The role of lipoprotein particles is to transport cholesterol from glial cells, where it is synthesised, to neurons, which require cholesterol for synaptic plasticity. The lipoprotein particles have a cholesterol-containing hydrophobic core, in which amyloid-β (Aβ) can be solubilised. The core is surrounded by a hydrophilic surface containing apolipoprotein E (APOE) which, as neurons bear receptors for APOE, determines the destination of the particles. The problem arises because the extracellular space is a narrow cleft, barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. We explain how lipoprotein particles could become trapped in the ageing extracellular matrix and that this primary abnormality results in reduced delivery of cholesterol to neurons leading to impaired synaptic plasticity, crucial for learning and memory. It can also explain extracellular Aβ accumulation, to which a microglial response generates a neurotoxic reaction, and intraneuronal tau aggregation, each of which exacerbate the problem. All these players have been known for many years to be important in Alzheimer’s pathogenesis but a single unifying mechanism to explain how they are linked has been lacking. This proposed mechanism, with entrapment of lipoproteins particles as key to the development of AD, can explain the failure of so many clinical trials and points out new directions to be taken.
format	article
author	Delphine Boche James AR Nicoll
author_facet	Delphine Boche James AR Nicoll
author_sort	Delphine Boche
title	Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
title_short	Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
title_full	Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
title_fullStr	Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
title_full_unstemmed	Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease
title_sort	hypothesis: entrapment of lipoprotein particles in the brain causes alzheimer’s disease
publisher	University of Münster / Open Journals System
publishDate	2021
url	https://doaj.org/article/9890ce4721294cc38b8e35d6308bff1a
work_keys_str_mv	AT delphineboche hypothesisentrapmentoflipoproteinparticlesinthebraincausesalzheimersdisease AT jamesarnicoll hypothesisentrapmentoflipoproteinparticlesinthebraincausesalzheimersdisease
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Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease

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