Ewha Med J.  2023 Oct;46(4):e17. 10.12771/emj.2023.e17.

Protective Effects of Statins against Alzheimer Disease

• Rezakhani L
• Salimi Z
• Zarei F
• Moradpour F
• Khazaei MR
• Khazaei M
• Pourjalili M

• KMID: 2547921
• DOI: http://doi.org/10.12771/emj.2023.e17

Abstract

Alzheimer disease (AD) is a common neurodegenerative disorder, characterized by memory impairment, dementia, and diminished cognitive function. This disease affects more than 20 million people worldwide. Amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are important pathological markers of AD. Multiple studies have indicated a potential association between elevated cholesterol levels and increased risk of AD, suggesting that lowering the cholesterol level could be a viable strategy for AD treatment or prevention. Statins, potent inhibitors of cholesterol synthesis, are widely used in clinical practice to decrease the plasma levels of LDL cholesterol in patients with hyperlipidemia. Statins are known to play a neuroprotective role in limiting Aβ pathology through cholesterol-lowering therapies. In addition to Aβ plaques and neurofibrillary tangles, the brains of AD patients exhibit signs of oxidative stress, neuroinflammatory responses, and synaptic disruption. Consequently, compounds with antioxidant, anti-inflammatory, and/or neuroprotective properties could be beneficial components of AD treatment strategies. In addition to lowering LDL cholesterol, statins have demonstrated therapeutic efficacy in various forms, including antioxidant, anti-inflammatory, and neuroprotective effects. These properties of statins are potential mechanisms underlying their beneficial effects in treating neurodegenerative diseases. Therefore, this review was conducted to provide an overview of the protective effects of statins against AD.

Keyword

Alzheimer disease; Hydroxymethylglutaryl-CoA reductase inhibitor; Neuroinflammatory diseases; Oxidative stress

Figure

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  Fig. 1. Synthesis of endogenous cholesterol. The HMGCR enzyme controls the rate of the mevalonate pathway and facilitates the conversion of HMG-CoA to mevalonate. Statins can significantly inhibit this enzyme. HMGCR, HMG-CoA reductase; IPP, isopentenyl pyrophosphate; GPP, geranyl pyrophosphate; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate.

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  Fig. 2. Dysfunctions associated with β-amyloid.

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  Fig. 3. Statins reduce oxidative stress in Alzheimer disease. The β-amyloid peptide increases the production of ROS by activating NOX. The Nrf2/HO-1 signaling pathway promotes expression of genes related to antioxidant enzymes and enhances antioxidant enzyme synthesis. Statins function as potent antioxidant compounds by activating the Nrf2/HO-1 pathway and inhibiting the NOX pathway. ROS, reactive oxygen species; NOX, nicotinamide adenine dinucleotide phosphate oxidase; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; BDNF, brain-derived neurotrophic factor; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase.

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  Fig. 4. Statins reduce neuroinflammation in Alzheimer disease. β-amyloid exerts neurotoxic effects by activating NF-κB, which in turn produces toxic inflammatory mediators, including cytokines. By decreasing NF-κB activity, statins lead to decreases in pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and COX-2. NF-κB, nuclear transcription factor kappa B; COX-2, cyclooxygenase 2.

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  Fig. 5. Statins can regulate synaptic plasticity via impacts on neurotrophic factors such as BDNF. Through both MVA pathway-dependent and pathway-independent mechanisms, statins can stimulate the activation of CREB signaling molecular pathways. HMGCR, HMG-CoA reductase; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; PPARα, peroxisome proliferator-activated receptor α; CREB, cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; MVA, mevalonate.

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  Fig. 6. Roles of GSK-3β in synaptic disruption. GSK-3β activation and subsequent tau hyperphosphorylation, CREB inhibition, and cholinergic system deficiency are involved in synaptic disruption. Statins can enhance synaptic plasticity by inhibiting GSK-3β activation. GSK-3β, glycogen synthase kinase 3 beta; CREB, cAMP response element-binding protein.

Reference

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