Astrocyte dysfunction in Alzheimer disease

Acosta, Crystal; Anderson, Hope D.; Anderson, Christopher M.

doi:10.1002/jnr.24075

Cited by 201 publications

(132 citation statements)

References 285 publications

(352 reference statements)

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“…The vasoactive substances PGE 2 and EETs can activate the potassium channels in the vascular smooth muscle cells after release from astrocytes end foot, resulting in vasodilatation and CBF increase (Attwell et al, 2010;Howarth, 2014;. These neurovascular pathways are crucial in understanding the neuropathic cascades that precede cognitive deterioration and dementia development (de la Torre, 2010), and have therefore, the potential to become new therapeutic targets in AD treatment (Zlokovic, 2005;van Norden et al, 2012;Acosta et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

et al. 2020

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Background: The astrocytic phospholipase A 2 (PLA 2 )-arachidonic acid (AA) pathway is crucial in understanding the reduction of cerebral blood flow (CBF) prior to cognitive deterioration. In complementary and alternative medicine, manual acupuncture (MA) is used as one of the most important therapies for Alzheimer's disease (AD). The beneficial effects of MA on CBF were reported in our previous study. However, the underlying molecular mechanism remains largely elusive.Objective: To investigate the effect of MA on the astrocytic PLA 2 -AA pathway in SAMP8 mice hippocampi.Methods: SAMP8 mice were divided into the SAMP8 control (Pc) group, the SAMP8 MA (Pm) group and the SAMP8 donepezil (Pd) group. SAMR1 mice were used as the SAMRl control (Rc) group. Mice in the Pd group were treated with donepezil hydrochloride at 0.65 µg/g. In the Pm group, MA was applied at Baihui (GV20) and Yintang (GV29) for 20 min. The above treatments were administered once a day for 26 consecutive days. The Morris water maze was applied to assess spatial learning and memory. Immunofluorescence staining, western blot and liquid chromatographytandem mass spectrometry were used to investigate the expression of related proteins and measure the contents of the metabolic intermediates of the PLA 2 -AA pathway.Results: Compared with that in the Rc group, the escape latency in the Pc group significantly increased (p < 0.01); whereas, the platform crossover number and percentage of time and swimming distance in the platform quadrant decreased (p < 0.01). The hippocampal expression of PLA 2 , cyclooxygenase-1, cytochrome P450 proteins 2C23 and the levels of AA, prostaglandin E 2 and epoxyeicosatrienoic acids of the Pc group was drastically higher than that in the Rc group (p < 0.01). These changes were reversed by MA and donepezil (p < 0.01 or p < 0.05). Frontiers in Neuroscience | www.frontiersin.org February 2020 | Volume 13 | Article 1354 Ding et al. Acupuncture Regulates PLA 2 -AA PathwayConclusion: MA can effectively improve the learning and memory abilities of SAMP8 mice and has a negative regulatory effect on the PLA 2 -AA pathway. We propose that the increase of the arterial tone, which is induced by the inhibition of vasodilatory pathway, may be a reason for the beneficial effect of MA on CBF.Keywords: manual acupuncture, Alzheimer's disease, astrocyte, hippocampus, phospholipase A 2 , arachidonic acid, cerebral blood flow absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Section: Introductionmentioning

confidence: 99%

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

et al. 2020

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“…Alzheimer's disease (AD) is the most common cause of dementia in the elderly (Grimm, Mett, Grimm, & Hartmann, 2017). In AD, as in many other neurodegenerative diseases, normal astrocytic processes are compromised, leading to altered neuronal functions and memory deficits (Acosta, Anderson, & Anderson, 2017). Whereas the majority of AD cases are late-onset (LOAD) without evidence of genetic inheritance, 1-6% of the cases manifest at an early age (early-onset, EOAD) and are caused by mutations in genes, such as presenilin-1 (PSEN1), responsible for the accumulation of toxic amyloid beta (Aβ) in the brain, representing the main pathological hallmark of AD (Grimm, Rothhaar, & Hartmann, 2012).…”

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confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate‐limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1‐mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742‐treated mice did not show altered astrocytic glial fibrillary acidic protein‐immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ‐induced impairment of long‐term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ‐agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

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“…It is interesting to note that in the CA1 subfields of the hippocampus, reactive astrocytes, proximal to Aβ plaques, have significantly higher GFAP expression than astrocytes distal to amyloid plaques [62,71]. Moreover, these distal astrocytes display atrophy [62], which is thought to occur before plaque formation, suggesting that astrocytes may be associated with early changes occurring during the development of AD [32].…”

Section: Astrocytes In Alzheimer's Diseasementioning

confidence: 99%

“…Dysregulation in the release of chemical neurotransmitters including glutamate, D-serine, GABA, as well as calcium in astrocytes leads to a disturbance in the normal communication between neurons and astrocytes and eventually impairs synaptic plasticity [32,71]. Moreover, the majority of hippocampal astrocytes (86%) in the AD brain express heme oxygenase (HO-1), while normal astrocytes almost do not express HO-1 at all (6-7%).…”

Section: Astrocytes In Alzheimer's Diseasementioning

confidence: 99%

“…Glycolysis in astrocytes is directly linked to the energy metabolism in neurons via the astrocyte-neuron lactate shuttle. There the lactate, produced in astrocytes, can be transferred to neurons as a supplement for their TCA cycle in mitochondria [32]. Therefore, neurons and astrocytes are intricately linked in their energy metabolism, and in mitochondrial function.…”

Section: Mitochondrial Function In Astrocytesmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes

Lampinen¹,

Belaya²,

Boccuni³

et al. 2018

Astrocyte - Physiology and Pathology

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The brain is one of the most energy-requiring organs in the human body. Mitochondria not only generate this energy, but are centrally involved critical cellular functions including maintenance of calcium homeostasis, synthesis of biomolecules, and cell signaling. Even though neurons and astrocytes preferentially use different energy substrates and metabolic pathways, these two cell types are intricately linked in their energy metabolism. Recently it has become clear that astrocytes have a key role in the regulation and support of the neuronal mitochondrial quality control, yet several questions remain unanswered to fully understand the mechanisms of mitochondrial function, transport, turnover and degradation in astrocytes. Alzheimer's disease is the most common neurodegenerative disorder, the exact mechanisms of which remain incompletely understood. The fact that astrocytic mitochondrial dysfunction is an early event in the pathogenesis of Alzheimer's disease suggests that more research on mitochondrial function and impairment is required in the hopes of disease alleviation in the future.

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Astrocyte dysfunction in Alzheimer disease

Cited by 201 publications

References 285 publications

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes

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