Statins: The Role in the Treatment and Prevention of Alzheimer's Neurodegeneration

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease commonly seen in the elderly and is characterized by progressive cognitive and physical decline. Current understanding of AD pathogenesis revolves around amyloid-β peptide (Aβ), a product of the sequential proteolytic cleavage of the transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretase, enzymes found predominantly in the cholesterol rich micro domains of the cell membrane. Several risk factors for AD are associated with cholesterol metabolism, including dyslipidaemia, coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability and show a favorable side effect profile overall. By competitive inhibition of hydroxymethyl co-enzyme A-reductase, statins reduce the production of cholesterol and isoprenoid intermediates including geranylgeranyl and farnesyl pyrophosphate. These isoprenoids modify recently translated proteins such as small GTPase molecules that are essential in numerous cell-signaling pathways, including vesicular trafficking and inflammation. In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function and by reducing neuroinflammation. Furthermore, epidemiological studies suggest that statins may reduce the incidence of AD. Consequently, statins, secondary of their anti-hypercholesterolaemic, plieotropic and anti-inflammatory effects, are being investigated for a potential therapeutic role. This review will discuss evidence for the role of statins in the treatment and prevention of AD neurodegeneration.

Age-Related Alterations in the Metabolic Profile in the Hippocampus of the Senescence-Accelerated Mouse Prone 8: A Spontaneous Alzheimer's Disease Mouse Model

“…One study indicated that the application of a cholesterol-reducing LXR agonist improved the quantity of presynaptic boutons [7], regulated neuroinflammation, and decreased Aβ accumulation [26]. The administration of statins has also been demonstrated to protect against AD [27, 28]. Neural membranes contain several classes of phosphoglycerides, which not only constitute their backbone but also provide them with a suitable environment.…”

Internalization of GluA2 and the underlying mechanisms of cognitive decline in aged rats following surgery and prolonged exposure to sevoflurane

“…1.5 MAC: orthopedic surgery plus 2 h exposure of 1.5 MAC sevoflurane, n = 6. celastrol reduced cell death and Ab production by increasing HSP-70 and Bcl-2 expression and reducing NFkB, COX-2, and GSK-3b expression and oxidative stress . Additionally, atorvastatin had therapeutic potential in a mouse model of postoperative cognitive dysfunction, evoking protection from hippocampal interleukin-1b, reducing hippocampal endothelial COX-2 and NF-kB activation, decreasing microglial reactivity, and enhancing the phosphorylation of GSK-3b Pac-Soo et al, 2011).…”

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

“…Atorvastatin and pitavastatin reduce the level of oxidative stress, as revealed by the presence of 4HNE and AGE, in AD mouse brains, and improve insulin signaling and LDLR/ApoE systems, as well as the serum adiponectin/leptin balance [163]. Statins, in addition to their antihypercholesterolemic, pleiotropic and antiinflammatory effects, are being investigated for a potential therapeutic role in AD, though clinical studies are contradictory [161,164]. In a group of AD patients recruited for pharmacoge nomic studies treated with a multifactorial therapy for 1 year [49], we evaluated the effects of Sardilipin (ESAR94010; LipoEsar ® ; 500 mg/day; nutraceuti (Figure 3).…”

“…Statins are neuroprotective in stroke, cerebral ischemia, AD, Parkinson's disease, multiple sclerosis, epilepsy and trau matic brain injury [160]. Statins are widely prescribed for their cholesterol lowering ability [161]. By competitive inhibition of HMGCoA reductase, statins reduce the production of cholesterol and isoprenoid intermediates, including geranylgeranyl and farnesyl pyrophosphate.…”