Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

Lewis, Terry L.; Cao, Dongfeng; Lu, Hailin; Mans, Robert; Su, Yan; Jungbauer, Lisa; Linton, MacRae F.; Fazio, Sergio; LaDu, Mary Jo; Li, Ling

doi:10.1074/jbc.m110.127829

Cited by 180 publications

(178 citation statements)

References 67 publications

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“…51) Recent studies with genetic modifications of apo AI in AD mouse models demonstrate that apo AI performs protective roles in memory and AD pathology. 92,93) Furthermore, a remarkable reduction of apo AI has been shown in the CSF and brain of schizophrenia patients. 94) Thus, apo AI incorporated into the brain from the circulation might play important roles in the CNS.…”

Section: Lipoproteins In the Cnsmentioning

confidence: 99%

“…162) However, it was recently reported that over-expression of human apo AI preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of AD. 92) In addition, a deficiency of apo AI in AD model mice (APPSwe/PS1DE9) accelerated the memory deficits and caused significant cerebral amyloid angiopathy. 93) Variation in the apo AI gene might also influence the age of onset and the risk of AD.…”

Section: Lipid Metabolism and Admentioning

confidence: 99%

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Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFunctions of the central nervous system (CNS) are performed mainly by neurons and glia-primarily astrocytes, microglia and oligodendrocytes. It has been thought for a long time that glia only passively support neurons, but we now know that glia actively attend to assist in neuronal functions like synaptogenesis and neurotransmission. 1) Although it was believed that ca. 90% of the cells in the brain are glia and the rest of cells are neurons, Azevedo et al. recently reported that the numbers of neurons and non-neuronal cells (glia) are close to equal in human adult brain.2) Brain is the most cholesterol-rich organ in the body, and cholesterol metabolism in the CNS is tightly regulated between neurons and glia. [3][4][5][6][7] Imbalances in the metabolism of lipids, especially cholesterol, are closely linked to the development of several neurodegenerative disorders such as Alzheimer's disease, 8,9) Niemann-Pick type C disease 10) and Smith-Lemli Opitz syndrome. 11,12) In this review the regulation of lipid metabolism and the roles of glial lipoproteins in the CNS will be discussed. LIPID HOMEOSTASIS IN THE CNSThe system of lipid metabolism and transport in the CNS is different from that in peripheral tissues because the CNS is segregated from the peripheral circulation by the blood-brain barrier (BBB).13) Although lipoprotein particles can cross the BBB in vivo in Drosophila, which has a functional BBB like that in vertebrates, 14) lipoproteins in the mouse, rat and human do not cross the BBB. Consequently, since labeled cholesterol peripherally administrated was not found in the CNS of mammals, 15,16) cholesterol in the CNS is derived from de novo synthesis inside of the CNS. Furthermore, in the plasma of subjects who had liver transplantation the genotype of apolipoprotein (apo) E was that of the donor, whereas the subjects retained the own apo E genotype in the cerebrospinal fluid (CSF).17) Moreover, lipoproteins in the CNS consist of only high density lipoprotein (HDL)-like particles in contrast to the circulation which contains very low density lipoproteins (VLDL), low density lipoproteins (LDL) and HDL. It is known that the HDL-like particles in the CNS are secreted from glia (glial lipoproteins), mainly astrocytes and microglia, under normal conditions, [18][19][20] however lipoproteins can be secreted from neurons in vitro 21,22) and in vivo 23) under some specific conditions. Unesterified cholesterol is the major sterol in the adult brain, and small amounts of desmosterol and cholesteryl ester are also present. The majority (70-80%) of cholesterol in the adult brain is in myelin formed by oligodendrocytes. 24)Thus, the activity of cholesterol synthesis in the CNS is the highest during the myelinogenesis. After myelination, cholesterol synthesis continues at very low level in the CNS, and occurs mainly in astrocytes. 5,13,24) Neurons do not efficiently synthesize cholesterol and rely on external source of cholesterol from astrocytes, 25) so that neurons take up cholesterol as lipoproteins via ...

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Section: Lipoproteins In the Cnsmentioning

confidence: 99%

Section: Lipid Metabolism and Admentioning

confidence: 99%

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Hayashi

2011

Biological & Pharmaceutical Bulletin

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“…Crossing of ApoA1 null mice with AD model mice resulted no change in amyloid deposition in the brain (Fagan et al 2004). Similarly, when ApoA1 overexpressing mice were crossed with AD model mice, no alteration in amyloid metabolism was observed (Lewis et al 2010). Our result presented here shows that expression of ApoA1 was downregulated in Hsp27 transgenic mice, indicating that Hsp27 might have a role in the regulation (directly or indirectly) of ApoA1 expression.…”

Section: Discussionsupporting

confidence: 55%

Abeta(1-42) enhances neuronal excitability and disrupts synaptic plasticity by altering glutamate-recycling

Varga¹

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“…1 and Table 1, the effects of cross-amyloid interactions between different amyloid proteins may vary substantially. TTR (59), CysC (67), and apoA-I (62) all suppress A␤ fibrillation and delay AD progression in mice (57,64). In contrast, ␣-syn (23), tau (28), and fibrinogen-␣ (95) promote A␤ toxicity and/or fibrillation and increase the risk of AD in mice (32) and/or patients (25,76).…”

Section: Implications Of A␤ Cross-amyloid Interactionsmentioning

confidence: 99%

“…Polymorphisms of the promoter region of apoA-I are associated with increased AD risk (63). In an AD mouse model, overexpression of apoA-I impaired learning and caused memory deficits (64).…”

Section: Apolipoprotein Aimentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

128

108

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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Overexpression of Human Apolipoprotein A-I Preserves Cognitive Function and Attenuates Neuroinflammation and Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer Disease

Cited by 180 publications

References 67 publications

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Lipid Metabolism and Glial Lipoproteins in the Central Nervous System

Abeta(1-42) enhances neuronal excitability and disrupts synaptic plasticity by altering glutamate-recycling

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

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