Neuronal LRP1 Knockout in Adult Mice Leads to Impaired Brain Lipid Metabolism and Progressive, Age-Dependent Synapse Loss and Neurodegeneration

Liu, Qiang; Trotter, Justin H.; Zhang, Juan; Peters, Melinda; Cheng, Hua; Bao, Jianxin; Han, Xianlin; Weeber, Edwin J.; Bu, Guojun

doi:10.1523/jneurosci.4067-10.2010

Cited by 220 publications

(232 citation statements)

References 53 publications

(80 reference statements)

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“…However, the role of LRP1-dependent cell signaling in CNS injury in vivo has not been extensively examined to date. Mice with conditional loss of LRP1 in postmitotic neurons exhibit alterations in brain lipid metabolism, synapse loss, and neurodegeneration (45). LRP1 also modulates amyloid precursor protein processing through interaction with apolipoprotein E (46,3).…”

Section: Discussionmentioning

confidence: 99%

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Yoon¹,

Niekerk²,

Henry³

et al. 2013

Journal of Biological Chemistry

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Background: LRP1 activation is neuroprotective in vitro. The role of LRP1 in axonal plasticity and regeneration is unknown. Results: LRP1-dependent cell signaling that includes TrkC activation promotes axonal growth in the CNS. Conclusion: LRP1 agonists promote regeneration after spinal cord injury. Significance: A significant role is established for LRP1 in axonal growth and regeneration after CNS injury, identifying a novel class of therapeutic targets for neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Yoon¹,

Niekerk²,

Henry³

et al. 2013

Journal of Biological Chemistry

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“…This finding may help explain the strong genetic link between the e4 isoform of the cholesterol carrier ApoE and Alzheimer disease (AD). Indeed, deletion of LRP1, the major receptor for ApoE on neurons, results in impaired dendritic spine development and neurodegeneration with aging (12). Overactivity of this pathway may also produce adverse effects.…”

mentioning

confidence: 99%

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Ferris

Perry

Moreira

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

160

117

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Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.T he brain is one of the most cholesterol-rich organs in the body, with cholesterol playing an important role in membrane fluidity, vesicle formation, and synaptogenesis (1). Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3-5).When cholesterol is abundant, SREBP2 precursor remains sequestered in the endoplasmic reticulum by SREBP cleavage activating protein (SCAP). As cholesterol is needed, SCAP shuttles SREBP2 to the Golgi for cleavage into a transcriptionally active form that translocates to the nucleus, binds to sterol regulatory elements in DNA, and activates transcription of enzymes of cholesterol synthesis (2). Insulin can regulate SREBP2 expression and activity, in part via two insulin-induced regulatory proteins, Insig1 and Insig2 (6, 7). Furthermore, in insulindeficient diabetes, there is a decrease in SREBP2 and SCAP in the brain leading to decreased brain cholesterol synthesis (8). We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).Among the subtypes of glia, astrocytes serve the most diverse roles, providing both structural support to neurons and playing a major role in maintaining the blood-brain barrier. In addition, astrocytes provide a variety of metabolic functions, including storage of glycogen and uptake of ions and neurotransmitters from the synaptic cleft (9, 10).Astrocytes/glial cells have also been suggested to play an important role in brain cholesterol metabolism. When neuronallike retinal ganglion cells are grown in culture and expose...

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“…Brain cholesterol is essential for synapse and dendrite formation [13,14] and axonal guidance [15] , as well as being crucial for the development and maintenance of neuronal plasticity [16][17][18] , synaptic vesicle transport [19] , and neurotransmitter release [20] . Cholesterol depletion in neurons impairs synaptic vesicle exocytosis, neuronal activity, and neurotransmission, and leads to dendritic spine and synapse degeneration [21][22][23] . Abnormal cholesterol metabolism is associated with many neurodegenerative diseases such as Niemann-Pick C disease, Huntington's disease, AD, and Parkinson's disease [24][25][26][27] .…”

Section: Major Lipid Classes and Functions In The Brainmentioning

confidence: 99%

“…Cholesterol depletion in neurons impairs synaptic vesicle exocytosis, neuronal activity, and neurotransmission, and leads to dendritic spine and synapse degeneration [21][22][23] . Abnormal cholesterol metabolism is associated with many neurodegenerative diseases such as Niemann-Pick C disease, Huntington's disease, AD, and Parkinson's disease [24][25][26][27] .…”

Section: Major Lipid Classes and Functions In The Brainmentioning

confidence: 99%

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Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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Neuronal LRP1 Knockout in Adult Mice Leads to Impaired Brain Lipid Metabolism and Progressive, Age-Dependent Synapse Loss and Neurodegeneration

Cited by 220 publications

References 53 publications

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Lipid metabolism in Alzheimer’s disease

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