Abstract5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer's disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-β (Aβ) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Aβ levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-β precursor protein (APP) levels and processing, or Aβ catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, Aβ formation, secondary to correspondent changes in γ-secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating γ-secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD. Keywordsγ-secretase; Tg2576; Aβ; amyloid-β precursor protein; leukotrienes Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive function and dementia. The pathological hallmarks in the AD brains are amyloid plaques in the extracellular parenchyma consisting mainly of Amyloid-β (Aβ) peptides (1), and intraneuronal tangles made of abnormally phosphorylated microtubule-associated tau protein (2).Increasing evidence from human and mouse models suggests that inflammation is an important player in the pathogenesis of AD (3). Eicosanoids, including prostaglandins and leukotrienes, derive from arachidonic acid by the action of cyclooxygenase (COX-1 and COX-2), lipoxygenase (12/15 lipoxygenase (12/15LO), and 5-lipoxygenase (5LO) enzymes. They have important proinflammatory functions and a large array of other biological activities (4). The roles of cyclooxygenases (5-8) and 12/15LO (9,10) in AD have been studied, but much less attention has been directed to the 5LO (11). Previously, it has been shown that 5LO is present in the central nervous system (CNS) in neurons and other cell types in mice (12) and rats (13,14). 5LO and leukotrienes in the CNS have neuromodulatory and neuroendocrine functions (14-16) and might play an important role in aging-associated neurodegenerative diseases (12,13). 5LO and its metabolites have been also been reported to be associated with excitotoxic injury (17,18) and cerebral ischemia (19). Taken together, these data would indirectly indicate that 5LO may have also a role in neurodegeneration, but only few studies have directly addressed this issue. It has been shown that 5LO promoter mutations cause a lower 5LO expression compared to wild-type (20). In a pilot study on the association of 5LO promoter polymorphism and the age of onset of AD, a trend toward higher frequency of wild-type 5LO promoter was f...
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. The vast majority cases of AD are sporadic, without clear cause, and a combination of environmental and genetic factors have been implicated. The hypothesis that homocysteine (Hcy) is a risk factor for AD was initially prompted by the observation that patients with histologically confirmed AD had higher plasma levels of Hcy, also called hyperhomocysteinemia (HHcy), than age-matched controls. Most evidence accumulated so far implicates HHcy as a risk factor for AD onset, but conflicting results also exist. In this review, we summarize reports on the relationship between HHCy and AD from epidemiological investigations, including observational studies and randomized controlled clinical trials. We also examine recent in vivo and in vitro studies of potential mechanisms whereby HHcy may influence AD development. Finally, we discuss possible reasons for the existing conflicting data, and provide suggestions for future studies.
Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimer’s disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Aβ) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Aβ precursor protein (APP), β - or α-secretase pathways, nor with the Aβ catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Aβ formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.
Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer's disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy).In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype.Compared with Tg2576 mice on regular chow, the ones receiving the diet-deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Aβ levels in the cortex and hippocampus, and an elevation of Aβ deposits in the same regions. No significant changes were observed for steady state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Aβ catabolic pathways, i.e IDE and neprilysin proteins, or the Aβ chaperone apolipoprotein E.Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Aβ levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.
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