ApoE isoform affects LTP in human targeted replacement mice

Trommer, Barbara L.; Shah, Chirag; Yun, Sung Hwan; Gamkrelidze, Georgi; Pasternak, Emily S.; Ye, Gui Lan; Sotak, M.L.; Sullivan, Patrick M.; Pasternak, Joseph F.; LaDu, Mary Jo

doi:10.1097/00001756-200412030-00020

Cited by 113 publications

(91 citation statements)

References 25 publications

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“…It is suggested that apoE4 is able to promote Aβ aggregation and/or reduce the clearance of amyloid plaques [44]. Moreover, it was observed that human apoE4 knock-in mice show a decrease in long-term potentiation, excitatory synaptic transmission and dendritic arborization, which determine impaired synaptic and cognitive functions [45][46][47][48]. These experimental data corroborate with clinical evidence, demonstrating that apoε4 homozygosity confers a substantial cognitive function decline in persons aged 35 years or older [49].…”

Section: Alzheimer's Diseasesupporting

confidence: 59%

Cholesterol Homeostasis Imbalance and Brain Functioning: Neurological Disorders and Behavioral Consequences

Lecis¹,

Segatto²

2014

Journal of Neurology and Neurological Disorders

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Section: Alzheimer's Diseasesupporting

confidence: 59%

Cholesterol Homeostasis Imbalance and Brain Functioning: Neurological Disorders and Behavioral Consequences

Lecis¹,

Segatto²

2014

Journal of Neurology and Neurological Disorders

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“…It has been shown in vitro and in vivo that APOE 4 inhibits clearance, facilitates production and promotes deposition of A ␤ , ultimately leading to plaque formation [34] . The ability to form memories is reduced in APOE 4 transgenic mice models when compared to wild-type mice [38] . The increased lipid burden within the brain and impaired lipid homeostasis may then contribute to increased oxidative stress and lead to cellular damage through lipid peroxidation, decreased vascular perfusion and development of an immune response.…”

Section: Apolipoprotein Ementioning

confidence: 96%

Inflammation and Anti-Inflammatory Strategies for Alzheimer’s Disease – A Mini-Review

et al. 2009

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Until recently, the central nervous system (CNS) has been thought to be an immune privileged organ. However, it is now understood that neuroinflammation is linked with the development of several CNS diseases including late-onset Alzheimer’s disease (LOAD). The development of inflammation is a complex process involving a wide array of molecular interactions which in the CNS remains to be further characterized. The development of neuroinflammation may represent an important link between the early stages of LOAD and its pathological outcome. It is proposed that risks for LOAD, which include genetic, biological and environmental factors can each contribute to impairment of normal CNS regulation and function. The links between risk factors and the development of neuroinflammation are numerous and involve many complex interactions which contribute to vascular compromise, oxidative stress and ultimately neuroinflammation. Once this cascade of events is initiated, the process of neuroinflammation can become overactivated resulting in further cellular damage and loss of neuronal function. Additionally, neuroinflammation has been associated with the formation of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of LOAD. Increased levels of inflammatory markers have been correlated with an advanced cognitive impairment. Based on this knowledge, new therapies aimed at limiting onset of neuroinflammation could arrest or even reverse the development of the disease.

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“…Features of AD pathology in these animals include reduced numbers of presynaptic terminals in mice expressing apoE4 with (54,64) or without (53,66,68) expression of human amyloid precursor protein (APP), increased plaque deposition in apoE4 mice expressing APP (64), increased phosphorylation of tau (65)(66)(67), impaired learning and memory (55,69), and altered long-term potentiation (77).…”

Section: Apoe and Admentioning

confidence: 99%

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

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

834

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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ApoE isoform affects LTP in human targeted replacement mice

Cited by 113 publications

References 25 publications

Cholesterol Homeostasis Imbalance and Brain Functioning: Neurological Disorders and Behavioral Consequences

Cholesterol Homeostasis Imbalance and Brain Functioning: Neurological Disorders and Behavioral Consequences

Inflammation and Anti-Inflammatory Strategies for Alzheimer’s Disease – A Mini-Review

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

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