Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons

Silva, Gisele S. Seixas da; Melo, Helen M.; Lourenco, Mychael V.; Silva, Natalia de M. Lyra e; Carvalho, Marcelo B. de; Alves-Leon, Soniza Vieira; Souza, Jorge Marcondes de; Klein, William L.; da‐Silva, Wagner Seixas; Ferreira, Sérgio T.; Felice, Fernanda G. De

doi:10.1074/jbc.m116.753525

Cited by 50 publications

(36 citation statements)

References 76 publications

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“…In cultured neurons, exposure to exogenous Aβ increases synuclein aggregation via a reduction in autophagy (Lin et al, 2016a ). Aβ has been shown to affect autophagy through lowered AMPK activation and impaired insulin sensitivity (Park et al, 2012 ; Lin et al, 2016a ; Seixas da Silva et al, 2017 ; Chang et al, 2018 ). Tau fragments can block chaperone-mediated autophagy through incomplete entry into the lysosome.…”

Section: Sex and Autophagy Disruption In Alzheimer's Diseasementioning

confidence: 99%

Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease

Congdon

2018

Front. Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia, with over 5. 4 million cases in the US alone (Alzheimer's Association, 2016). Clinically, AD is defined by the presence of plaques composed of Aβ and neurofibrillary pathology composed of the microtubule associated protein tau. Another key feature is the dysregulation of autophagy at key steps in the pathway. In AD, disrupted autophagy contributes to disease progression through the failure to clear pathological protein aggregates, insulin resistance, and its role in the synthesis of Aβ. Like many psychiatric and neurodegenerative diseases, the risk of developing AD, and disease course are dependent on the sex of the patient. One potential mechanism through which these differences occur, is the effects of sex hormones on autophagy. In women, the loss of hormones with menopause presents both a risk factor for developing AD, and an obvious example of where sex differences in AD can stem from. However, because AD pathology can begin decades before menopause, this does not provide the full answer. We propose that sex-based differences in autophagy regulation during the lifespan contribute to the increased risk of AD, and greater severity of pathology seen in women.

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Section: Sex and Autophagy Disruption In Alzheimer's Diseasementioning

confidence: 99%

Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease

Congdon

2018

Front. Neurosci.

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“…In addition, tau misaggregation also occurs independently of Aβ [121]. Moreover, there are conflicting reports regarding the effect of Aβ on AMPK; some reports say Aβ stimulates AMPK [122,123] and some others say the effect is inhibitory [124][125][126][127]. erefore, before making these speculations, two things require clarification: (i) the exact effect of Aβ on AMPK whether it is stimulatory or inhibitory; and (ii) the effect AMPK on tau phosphorylation via its downstream molecules should be explored.…”

Section: Ampk and Tauopathymentioning

confidence: 99%

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Assefa

Tafere

Wondafrash

et al. 2020

BioMed Research International

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Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

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“…AMP-activated kinase (AMPK) is a key enzyme in energy sensing and metabolic reprogramming under cellular energy restriction, which is associated with some peripheral metabolic diseases, including diabetes. An impaired AMPK function has been linked recently to certain neurological disorders, such as AD [ 97 ]. The intracellular ATP levels and AMPK activity were decreased in cultured hippocampal neurons already after short-term exposure to AβOs.…”

Section: Cellular Receptors Related To Aβos Activitymentioning

confidence: 99%

“…The intracellular ATP levels and AMPK activity were decreased in cultured hippocampal neurons already after short-term exposure to AβOs. This AβO-dependent reduction in AMPK activity is also mediated by glutamate receptors NMDARs, which results in removal of glucose transporters (GLUTs) from the surfaces of hippocampal neurons [ 97 ].…”

Section: Cellular Receptors Related To Aβos Activitymentioning

confidence: 99%

Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease

Mroczko

Groblewska

Litman‐Zawadzka

et al. 2018

IJMS

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It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients’ brain composed of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aβ and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AβOs) aggregation in the pathogenesis of AD. Moreover, binding of AβOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AβO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aβ oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AβO receptors related to toxic activity of oligomers.

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Amyloid-β oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons

Cited by 50 publications

References 76 publications

Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease

Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease

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