geranylgeranyl-pyrophosphate and Alzheimer-Disease

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer's disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Ab) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD.Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only amyloid precursor protein and Ab. The purpose of this review, therefore, was to examine the above-mentioned issues, discuss the pros and cons of the cholesterol-AD hypothesis, involvement of other lipids in the mevalonate pathway, and consider that AD may impact cholesterol homeostasis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Astrocytes; Cell Membrane; Cells, Cultured; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Humans; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mice; Models, Biological; Neurons; Polyisoprenyl Phosphates; Rabbits; Sesquiterpenes

The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP)ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i.e., protein tau phosphorylated) production in the brain. In this study, a significant positive correlation was observed between the synthases mRNA prevalence and disease status (FPPS, p < 0.001, n = 123; GGPPS, p < 0.001, n = 122). The levels of mRNA for hFPPS and hGGPPS were found to significantly correlate with the amount of p-Tau protein levels (p < 0.05, n = 34) and neurofibrillary tangle density (p < 0.05, n = 39) in the frontal cortex. Interestingly, high levels of hFPPS and hGGPPS mRNA prevalence are associated with earlier age of onset in AD (p < 0.05, n = 58). Together, these results suggest that accumulation of p-Tau in the AD brain is related, at least in part, to increased levels of neuronal isoprenoids.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; cdc42 GTP-Binding Protein; Cerebellum; Farnesyltranstransferase; Female; Frontal Lobe; Geranyltranstransferase; Humans; Male; Mevalonic Acid; Neurofibrillary Tangles; Polyisoprenyl Phosphates; Protein Prenylation; rhoA GTP-Binding Protein; Sesquiterpenes; tau Proteins; Terpenes

There is keen interest in the role of the isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) in protein prenylation and cell function in Alzheimer's disease (AD). We recently reported elevated FPP and GGPP brain levels and increased gene expression of FPP synthase (FPPS) and GGPP synthase (GGPPS) in the frontal cortex of AD patients. Cholesterol levels and gene expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase were similar in AD and control samples, suggesting that homeostasis of FPP and GGPP but not cholesterol is specifically targeted in brain tissue of AD patients (Neurobiol Dis 2009 35:251-257). In the present study, it was determined if cellular levels of FPP, GGPP, and cholesterol affect beta-amyloid (Abeta) abundance in SH-SY5Y cells, expressing human APP695. Cells were treated with different inhibitors of the mevalonate/isoprenoid/cholesterol pathway. FPP, GGPP, cholesterol, and Abeta(1-40) levels were determined, and activities of farnesyltransferase and geranylgeranyltransferase I were measured. Inhibitors of different branches of the mevalonate/isoprenoid/cholesterol pathway as expected reduced cholesterol and isoprenoid levels in neuroblastoma cells. Abeta(1-40) levels were selectively reduced by cholesterol synthesis inhibitors but not by inhibitors of protein isoprenylation, indicating that changes in cholesterol levels per se and not isoprenoid levels account for the observed modifications in Abeta production.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Androstenes; Animals; Anticholesteremic Agents; Brain; Cell Line; Cholesterol; Enzyme Inhibitors; Humans; Mevalonic Acid; Neuroblastoma; Peptide Fragments; Polyisoprenyl Phosphates; Sesquiterpenes

Post-translational modification of small GTPases by farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP) has generated much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. Prenylated proteins have been identified in numerous cell functions and elevated levels of FPP and GGPP have been previously proposed to occur in Alzheimer disease (AD) but have never been quantified. In the present study, we determined if the mevalonate derived compounds FPP and GGPP are increased in brain grey and white matter of male AD patients as compared with control samples. This study demonstrates for the first time that FPP and GGPP levels are significantly elevated in human AD grey and white matter but not cholesterol, indicating a potentially disease-specific targeting of isoprenoid regulation independent of HMG-CoA-reductase. Further suggesting a selective disruption of FPP and GGPP homeostasis in AD, we show that inhibition of HMG-CoA reductase in vivo significantly reduced FPP, GGPP and cholesterol abundance in mice with the largest effect on the isoprenoids. A tentative conclusion is that if indeed regulation of FPP and GGPP is altered in AD brain such changes may stimulate protein prenylation and contribute to AD neuropathophysiology.

Topics: Acyl Coenzyme A; Aged; Aged, 80 and over; Alzheimer Disease; Animals; Brain; Cholesterol; Farnesyltranstransferase; Frontal Lobe; Geranyltranstransferase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Inbred C57BL; Myelin Sheath; Polyisoprenyl Phosphates; Sesquiterpenes; Simvastatin

Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration- and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-alpha. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-alpha but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.

Topics: Alzheimer Disease; Animals; CD11b Antigen; Cell Proliferation; Cell Shape; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Lovastatin; Mevalonic Acid; Microglia; Polyisoprenyl Phosphates; Rats; Rats, Sprague-Dawley; rho GTP-Binding Proteins; Simvastatin; Terpenes; Tumor Necrosis Factor-alpha

Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.

Topics: Alzheimer Disease; Animals; Apoptosis; Blotting, Western; Cell Culture Techniques; Cell Survival; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Hippocampus; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Situ Nick-End Labeling; Neurons; Phosphorylation; Polyisoprenyl Phosphates; Rats; Rats, Wistar; tau Proteins

Apolipoprotein E (ApoE) genotype modulates the risk of Alzheimer's disease. ApoE has been shown essential for amyloid beta-peptide fibrillogenesis and deposition, a defining pathological feature of this disease. Because astrocytes and microglia represent the major source of extracellular apoE in brain, we investigated apoE secretion by glia. We determined that protein prenylation is required for apoE release from a continuous microglial cell line, primary mixed glia, and from organotypic hippocampal cultures. Using selective protein prenylation inhibitors, apoE secretion was found to require protein geranylgeranylation. This prenylation involved a protein critical to apoE secretion, not apoE proper. ApoE secretion could also be suppressed by inhibiting synthesis of mevalonate, the precursor to both types of protein prenylation, using hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins). Recent reports have described the beneficial effects of statins on the risk of dementia. Our finding that protein geranylgeranylation is required for apoE secretion in the brain parenchyma provides another contributing mechanism to explain the effective properties of statins against the development of dementia. In this model, statin-mediated inhibition of mevalonate synthesis, an essential reaction in forming geranylgeranyl lipid, would lower extracellular levels of parenchymal apoE. Because apoE has been found necessary for plaque development in transgenic models of Alzheimer's disease, suppressing apoE secretion by statins could reduce plaques and, in turn, improve cognitive function.

Topics: Alkyl and Aryl Transferases; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Apolipoproteins E; Astrocytes; Brain; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Farnesyltranstransferase; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mevalonic Acid; Mice; Mice, Transgenic; Microglia; Neuroglia; Polyisoprenyl Phosphates; Protein Prenylation