Statins Reduce Amyloid-β Production through Inhibition of Protein Isoprenylation

Abstract

Epidemiological evidence suggests that long term treatment with hydroxymethylglutaryl-CoA reductase inhibitors, or statins, decreases the risk for developing Alzheimer disease (AD). However, statin-mediated AD protection cannot be fully explained by reduction of cholesterol levels. In addition to their cholesterol lowering effects, statins have pleiotropic actions and act to lower the concentrations of isoprenoid intermediates, such as geranylgeranyl pyrophosphate and farnesyl pyrophosphate. The Rho and Rab family small G-proteins require addition of these isoprenyl moieties at their C termini for normal GTPase function. In neuroblastoma cell lines, treatment with statins inhibits the membrane localization of Rho and Rab proteins at statin doses as low as 200 nM, without affecting cellular cholesterol levels. In addition, we show for the first time that at low, physiologically relevant, doses statins preferentially inhibit the isoprenylation of a subset of GTPases. The amyloid precursor protein (APP) is proteolytically cleaved to generate ␤-amyloid (A␤), which is the major component of senile plaques found in AD. We show that inhibition of protein isoprenylation by statins causes the accumulation of APP within the cell through inhibition of Rab family proteins involved in vesicular trafficking. Moreover, inhibition of Rho family protein function reduces levels of APP C-terminal fragments due to enhanced lysosomal dependent degradation. Statin inhibition of protein isoprenylation results in decreased A␤ secretion. In summary, we show that statins selectively inhibit GTPase isoprenylation at clinically relevant doses, leading to reduced A␤ production in an isoprenoid-dependent manner. These studies provide insight into the mechanisms by which statins may reduce AD pathogenesis.

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

“…Several studies suggest that statins may regulate the α-secretase activity either by their cholesterol-lowering effects [23,24] or by impairment of the isoprenoid pathway [24][25][26]. Comparison of these data is complicated by the fact that studies were performed under different experimental conditions.…”

“…Several reports described the involvement of the isoprenoid pathway in AβPP proteolytic processing after statin treatment [24,25]. To investigate the involvement of the isoprenoid pathway in statin-mediated α-secretase activation, SK-N-MC cells were treated with lovastatin in the presence of 200 µM mevalonate or with farnesyltransferase (L-744,832) and geranylgeranyltransferase (GGTI-286) inhibitors.…”

“…The enzymes generating Aβ, the β-and γ-secretases, operate best in a high-cholesterol environment favoring Aβ production, whereas a reduction of cellular cholesterol leads to a decrease in Aβ production [19,[21][22][23]. Various cell culture studies showed that cholesterol reduction by statin treatment promotes the non-amyloidogenic α-secretase pathway by increasing the formation of neuroprotective sAβPPα and by decreasing Aβ production [23][24][25]. Despite of all these findings, the mechanism of statin action on secretases still remains unclear.…”

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

“…The expression of genes for the proteins that are involved in isoprenoid synthesis, along with isoprenoids themselves, have been reported to be elevated in the frontal cortex of AD patients [42,43] and have been implicated in inflammation and oxidative stress [44][45][46]. HMGCR inhibitors (such as statins) have been shown to reduce Ab generation by depleting isoprenoids independent of cholesterol levels [47][48][49]. This suggests that up-regulation of HMGCR in SH-SY5Y cells by Ab 42 may increase the isoprenoid levels for an inflammatory response.…”

Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

“…While the effects of statins on plasma lipid levels are well described, the actual mechanisms by which these and other effects are obtained are not always clear (2). Statins have pleiotropic effects at the physiological level (e.g., depression, insomnia, neuropathy, antiinflammatory, and antiatherogenic effects) as well as at the cellular (e.g., interference with lysosomal functions) and biochemical levels (e.g., reduced isoprenylation of proteins and inhibition of GTPases) (3)(4)(5)(6). Furthermore, statins are increasingly being considered as anti-cancer drugs because of their effects on the RAS superfamily of GTPases (1) and have recently proven protective against heart failure in patients where cholesterol levels are not elevated (7).…”