APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Brandon, J. Anthony; Farmer, Brandon C.; Williams, Holden C.; Johnson, Lance A.

doi:10.3389/fnagi.2018.00180

Cited by 56 publications

(42 citation statements)

References 97 publications

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“…The current finding that apoE4 carriers are impaired relative to apoE3 carriers in cognitive parameters is consistent with previous studies in mice [81][82][83] and humans [84][85][86]. The fact that the HFD impaired apoE3 mice is consistent with many studies that have shown that WT mice are impaired following the HFD in cognitive [87,88], sensory [89], and motor paradigms [89].…”

Section: Discussionsupporting

confidence: 92%

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Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Koren-Iton

Salomon-Zimri

Smolar

et al. 2020

IJMS

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Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

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Section: Discussionsupporting

confidence: 92%

“…This test was performed as described in [81,106] and is based on the natural tendency of rodents to investigate a novel object. For the habituation phase, the mice were first placed in an arena (50 × 50 cm with 40 cm high walls) in the absence of objects.…”

Section: Short-term Memory Measurementsmentioning

confidence: 99%

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Koren-Iton

Salomon-Zimri

Smolar

et al. 2020

IJMS

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“…We found E4 astrocytes to exhibit a lower OCR compared to E3 at all time points (Figure 4E). This lower OCR is likely primarily due to a decreased rate of glucose oxidation, as E4 is strongly associated with a phenotype of glucose hypometabolism [4,37]. When we specifically calculated the contribution of FA oxidation to OCR by comparing basal OCR in palmitate treated versus BSA treated astrocytes, we found that E4 astrocytes utilize significantly less exogenously supplied FA as part of their basal respiration (Figure 4F).…”

Section: Resultsmentioning

confidence: 97%

“…In addition to established effects on AD neuropathology, APOE genotype is also recognized as a strong modulator of cerebral metabolism [3,4,5,6]. In fact, cognitively normal E4+ individuals demonstrate alterations in cerebral fatty acid (FA) and carbohydrate metabolism congruent with AD patients [4,7]. Understanding the metabolic effects of apoE in the brain may be a critical step in discovering the underlying mechanism(s) of E4-driven AD risk.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation

Farmer

Kluemper

Johnson

2019

Cells

118

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Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype.

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“…Reportedly, polymorphism of ApoE allele, especially ApoE ε4, attributes to risk of AD development by increasing Aβ and Tau aggregation, whereas ApoE ε2 exhibits protective effects on risk of AD development (Verghese et al, 2011). Moreover, ApoE ε4 induces dysregulation of cerebral metabolism by decreasing lipid and glucose metabolism (Brandon et al, 2018). Interestingly, the control of insulin and plasma glucose by ghrelin administration can vary depending on the details of administration (i.e., duration, route, and dose) (Nieminen and Mustonen, 2004;Theander-Carrillo et al, 2006;Barazzoni et al, 2007a;Goshadrou et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The Potential Roles of Ghrelin in Metabolic Syndrome and Secondary Symptoms of Alzheimer’s Disease

Kim¹,

Nam²,

Shin³

et al. 2020

Front. Neurosci.

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Although the major causative factors of Alzheimer's disease (AD) are the accumulation of amyloid β and hyperphosphorylated tau, AD can also be caused by metabolic dysfunction. The major clinical symptom of AD is cognitive dysfunction. However, AD is also accompanied by various secondary symptoms such as depression, sleep-wake disturbances, and abnormal eating behaviors. Interestingly, the orexigenic hormone ghrelin has been suggested to have beneficial effects on AD-related metabolic syndrome and secondary symptoms. Ghrelin improves lipid distribution and alters insulin sensitivity, effects that are hypothesized to delay the progression of AD. Furthermore, ghrelin can relieve depression by enhancing the secretion of hormones such as serotonin, noradrenaline, and orexin. Moreover, ghrelin can upregulate the expression of neurotrophic factors such as brain-derived neurotrophic factor and modulate the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β. Ghrelin alleviates sleep-wake disturbances by increasing the levels of melatonin, melanin-concentrating hormone. Ghrelin reduces the risk of abnormal eating behaviors by increasing neuropeptide Y and γ-aminobutyric acid. In addition, ghrelin increases food intake by inhibiting fatty acid biosynthesis. However, despite the numerous studies on the role of ghrelin in the AD-related pathology and metabolic disorders, there are only a few studies that investigate the effects of ghrelin on secondary symptoms associated with AD. In this mini review, our purpose is to provide the insights of future study by organizing the previous studies for the role of ghrelin in AD-related pathology and metabolic disorders.

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APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Cited by 56 publications

References 97 publications

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation

The Potential Roles of Ghrelin in Metabolic Syndrome and Secondary Symptoms of Alzheimer’s Disease

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