Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-beta (Abeta) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS).
We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia.
Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Abeta42, Abeta40, soluble amyloid beta protein precursor (sAbetaPP) alpha or beta, or F2-isoprostanes.
Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.
"These findings are consistent with the quasi-absence of cortical neurofibrillary tangles in autopsyconfirmed cognitively intact subjects who had used statins for several years as opposed to non-users (Li et al., 2007). Interestingly, although statins can cause a significant reduction in phosphorylated tau levels in the cerebrospinal fluid of patients treated for hypercholesterolemia, they do not seem to affect β-amyloid levels (Riekse et al., 2006). Higher concentrations of both FPP and GGPP in the brain tissues of aged mice vs. younger mice have also been observed (Hooff et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.
Frontiers in Chemistry 07/2014; 2:50. DOI:10.3389/fchem.2014.00050
"Our preliminary animal studies failed to show that statin treatment affects Aβ levels in the blood and CSF (unpublished data), whereas brain Aβ level was reduced by a statin (Shinohara et al., 2010). These experimental results are consistent with the results of clinical studies, reporting no change in Aβ levels in CSF and plasma by statin use in AD patients and cognitively normal adults (Ishii et al., 2003; Sjogren et al., 2003; Hoglund et al., 2004, 2005a; Riekse et al., 2006; Carlsson et al., 2008; Serrano-Pozo et al., 2010). These results suggest that Aβ levels in CSF and plasma would not reflect the " anti-Aβ " effect of statins in the brain. "
[Show abstract][Hide abstract] ABSTRACT: The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.
"However in patients without dementia, treatment with simvastatin and pravastatin for 14 weeks did not significantly alter CSF levels of either Aβ40 or 42 or t-tau . Other studies also confirm steady Aβ and t-tau levels with statins  , although some reports differ with respect to p-tau  . NMDA receptor antagonists prevent against excitotoxicity, and therefore, cell death; while not yet proven, these agents may in fact lower t-tau CSF levels, proposed markers of neuronal death. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed. Biomarkers are multidimensional and have the potential to aid in various facets of AD such as diagnostic prediction, assessment of disease stage, discrimination from normally cognitive controls as well as other forms of dementia, and therapeutic efficacy of AD drugs. To date, biomarker research has focused on plasma and cerebrospinal fluid (CSF), two bodily fluids believed to contain the richest source of biomarkers for AD. CSF is the fluid surrounding the central nervous system (CNS), and is the most indicative obtainable fluid of brain pathology. Blood plasma contains proteins that affect brain processes from the periphery, as well as proteins/peptides exported from the brain; this fluid would be ideal for biomarker discovery due to the ease and non-invasive process of sample collection. However, it seems reasonable that biomarker discovery will result in combinations of CSF, plasma, and other fluids such as urine, to serve the aforementioned purposes. This review focuses on proteins and peptides identified from CSF, plasma, and urine that may serve as biomarkers in AD.
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