BackgroundThe 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice.Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology.ResultsOur results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2.ConclusionsThese data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.
Objective
The 5-lipoxygenase (5LO) enzyme is up-regulated in Alzheimer’s disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.
Methods
To this end, we generated triple transgenic mice (3xTg-AD) over-expressing neuronal 5LO and investigated their phenotype.
Results
Compared with controls, 3xTg-AD mice over-expressing 5LO manifested an exacerbation of memory deficits, plaques and tangles pathologies. The elevation in Aβ was secondary to an up-regulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5-LO-dependent tau phosphorylation, which was independent of the effect on Aβ.
Interpretation
Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.
The 5-Lipoxygenase (5LO) is upregulated in Alzheimer’s disease (AD), and in vivo modulates the amyloidotic phenotype of APP transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue we used a genetic and a pharmacologic approach by generating 3xTg mice deficient for 5LO, and administering 3xTg mice which a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life these mice had a significant reduction of Aβ and tau pathology.Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this proetin as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.
Background
The 5-lipoxygenase (5LO) is a protein widely distributed in the central nervous system where modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer’s disease. However, no data are available as to whether 5LO is elevated in human tauopathy, or if it directly influences tau pathology in a relevant model of the disease.
Methods
We assayed 5LO levels in brain samples from tauopathy patients and transgenic tau mice, and evaluated the effect that 5LO pharmacological inhibition has on the phenotype of these mice.
Results
The 5LO is up-regulated in human tauopathy and transgenic tau mice brains. Pharmacological blockade of 5LO in tau mice results in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism.
Conclusions
Our results establish 5LO as a key player in the development of the tau pathology phenotype, and a novel viable therapeutic target for the pharmacological treatment of human tauopathy.
SUMMARY
Background
A major hallmark feature of Alzheimer’s disease (AD) is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with the γ-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are not known.
Methods
Post-mortem brain tissues from AD patients, transgenic mouse models of AD and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis.
Results
We identify a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrate that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD, and that the process is biologically relevant since its pharmacological blockade reduces Aβ pathology in vivo.
Interpretation
Our data by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production establish it as a novel, attractive and viable Aβ lowering therapeutic target for AD.
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