Blockade of HMG‐CoA reductase activity causes changes in microtubule‐stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease

Abstract

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.

A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

“…Vulnerable neurons in AD brain were shown to contain levels of free cholesterol that were higher than levels in healthy neurons (28), and cholesterol accumulates in the senile plaques (29), suggesting oversynthesis of cholesterol. Statins were associated with lower risk for AD if given at middle age, although the exact mechanism of their action is not yet clear (30,31). Another possible explanation for the effect of statins is regulating the synthesis of cholesterol while preserving the FPP group for nonsterol isoprenoids such as heme-a.…”

“…Another possible explanation for the effect of statins is regulating the synthesis of cholesterol while preserving the FPP group for nonsterol isoprenoids such as heme-a. However, it is important to emphasize that statins do not reach a high enough concentration in the brain to completely inhibit hydroxymethylglutarylCoA reductase; otherwise, cell death could occur (31). In the light of the complexity of the metabolism of cholesterol and its inf luence on the pool of FPP, more research on statins and nonisoprenoids in AD is required to understand the inf luence of statins on metabolism beyond cholesterol.…”

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

“…Mevalonate, the concentration of which is rapidly lowered by HMG-CoA reductase inhibitors (43,44), regulates diverse cellular activities in part by generating farnesyl diphosphate and geranylgeranyl diphosphate, compounds that provide for lipid modification (prenylation) of proteins, including those belonging to the Rho and Ras families. Blocking prenylation of these regulatory agents provides a plausible route whereby statins could activate microglia.…”

β-Amyloid Inhibits Protein Prenylation and Induces Cholesterol Sequestration by Impairing SREBP-2 Cleavage

“…long-term potentiation in hippocampal slices (Matthies et al, 1997;Kotti et al, 2006Kotti et al, , 2008, the increase in Tau hyperphosphorylation , and the prevention of statininduced neurotoxicity by isoprenoids (Tanaka et al, 2000;Meske et al, 2003;Schulz et al, 2004). Protein prenylation is important for APP trafficking and cleavage.…”