Statins Reduce the Neurofibrillary Tangle Burden in a Mouse Model of Tauopathy

Abstract

Statin treatment has been associated with a reduced risk of Alzheimer disease and decreased amyloid deposition in mouse models. No animal studies have reported effects of statins on tau aggregates and neurofibrillary tangles (NFTs), the pathological hallmarks of Alzheimer disease that correlate with dementia. We investigated the effect of statins on NFTs in a transgenic mouse tauopathy model and found the following: 1) 1-month treatment with the blood-brain barrier-permeable agent simvastatin in normocholesterolemic aged mice significantly reduced the NFT burden and decreased lectin-positive microglia; 2) simvastatin significantly decreased NFTs and improved T-maze performance in young animals treated for 8 months; 3) treatment of hypercholesterolemic mice for 5 months with blood-brain barrier-impermeable atorvastatin markedly reduced the NFT burden and decreased lectin-positive microglia; 4) nonstatin cholesterol-lowering strategies showed a modest NFT decrease compared with statin treatment; and 5) there was a positive correlation between microglial and NFT burden (r = 0.8). Together, these results suggest that statins reduce NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long- and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions. The decrease in microglia, coupled with the limited effect of nonstatin cholesterol lowering, suggests that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties. Statins may provide therapy against NFTs in tauopathies, particularly when NFTs are the major neuropathologic component.

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…In a similar design, another lipid-lowering drug, ezetimibe (10 mg/kg, orally for 15 days) also significantly attenuated STZ-icv induced memory deficits and oxidative stress changes in mice (Dalla et al 2009). The effect of statins on tau aggregates and neurofibrillary tangles (NFT) has been investigated in a transgenic mouse tauopathy model where it was found that statins reduced NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long-and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions (Boimel et al 2009). Results suggest that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties.…”

Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

“…Recently, it has been reported that statins could [19] . Of particular interest, some studies have shown that statin treatment markedly reduced Tau levels and NFTs in cellular and mouse models of tauopathy [18,36] . A clinical observation showed that simvastatin decreased the amount of phosphorylated Tau in the cerebrospinal fluid of AD patients [37] .…”

“…Evidence from cell culture experiments and animal studies has suggested that statins have many pleiotropic effects, such as reducing Aβ production, suppressing inflammatory responses, protecting neurons from Aβ-induced neurotoxicity, apoptosis and oxidative stress, and promoting synaptogenesis [14][15][16][17] . Recently, a transgenic mouse model of tauopathy showed a reduction in NFTs in response to statin treatment in both early and late stages of disease progression [18] . It has been reported that statins reduce the number of phosphorylated Tau-positive neurites in aged amyloid precursor protein (APP) transgenic mice [19] .…”

In Search of Therapeutic Solutions for Alzheimer’s Disease

“…On the other hand, recent anti-amyloid strategies, have failed in their efficacy or safety on their last development phases (Holmes et al, 2008). Statins appear to reduce the burden of NFTs, but clinical studies are not conclusive (Rojo et al, 2006;Boimel et al, 2009). In the whole context, tau based therapies represent a potential therapeutic target, specifically those that that diminish its aggregation, or alter its hyperphosphorylation (Alvarez et al, 2001).…”