Age-dependent effects of microglial inhibition in vivo on Alzheimer’s disease neuropathology using bioactive-conjugated iron oxide nanoparticles

Abstract

BackgroundTau dysfunction is believed to be the primary cause of neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease, Pick’s disease, frontotemporal dementia and Parkinsonism. The role of microglial cells in the pathogenesis of tauopathies is still unclear. The activation of microglial cells has been correlated with neuroprotective effects through the release of neurotrophic factors and through clearance of cell debris and phagocytosis of cells with intracellular inclusions. In contrast, microglial activation has also been linked with chronic neuroinflammation contributing to the development of neurodegenerative diseases such as tauopathies. Microglial activation has been recently reported to precede tangle formation and the attenuation of tau pathology occurs after immunosuppression of transgenic mice.MethodsHere we report the specific inhibition of microglial cells in rTg4510 tau-mutant mice by using fibrin γ377-395 peptide conjugated to iron oxide (γ-Fe2O3) nanoparticles of 21 ± 3.5 nm diameter.ResultsStabilization of the peptide by its covalent conjugation to the γ-Fe2O3 nanoparticles significantly decreased the number of the microglial cells compared to the same concentration of the free peptide. The specific microglial inhibition induces different effects on tau pathology in an age dependent manner. The reduction of activation of microglial cells at an early age increases the number of neurons with hyperphosphorylated tau in transgenic mice. In contrast, reduction of activation of microglial cells reduced the severity of the tau pathology in older mice. The number of neurons with hyperphosphorylated tau and the number of neurons with tangles are reduced than those in animals not receiving the fibrin γ377-395 peptide-nanoparticle conjugate.ConclusionsThese results demonstrate a differential effect of microglial activity on tau pathology using the fibrin γ377-395 peptide-nanoparticle conjugate, depending on age and/or stage of the neuropathological accumulation and aggregation.

Iron Oxide Based Nanoparticles for Magnetic Hyperthermia Strategies in Biological Applications

“…Another approach is to fight tau dysfunctions, which are suspected to be behind many disorders like Alzheimer′s disease, Pick's disease or Parkinsonism. In a recent work, Glat et al72 demonstrated the beneficial effect of a fibrin peptide conjugated to γ‐Fe 2 O 3 (maghemite) in reducing the activation of microglial cells in rTg4510 mutant mice, which resulted in a reduced number of neurons with the undesired tangles compared to animals not treated with the therapeutic nanoparticles.…”

Application of Iron Oxide Nanoparticles in the Diagnosis and Treatment of Neurodegenerative Diseases With Emphasis on Alzheimer’s Disease

“…Adams et al (2007) conjugated fibrin γ377-395 peptide [one fibrin-derived peptide that can inhibit microglial activity in vivo specifically to iron oxide (γ-Fe 2 O 3 ) nanoparticles with diameters 21 ± 3.5 nm] in order to counteract the short half-life of the peptide. The study showed that, compared to the free peptide of the same concentration, γ-Fe 2 O 3 nanoparticles could specifically inhibit the microglial cells in rTg4510 tau-mutant mice, supporting the fact that the nanoparticles can be used for the delivery of substances to the brain and for providing a possible therapeutic strategy to neurodegenerative tauopathies (Glat et al, 2013). Kouyoumdjian et al (2013) reported a biomimetic path using glyconanoparticles-SPIO to detect Aβ.…”

<p>Effect of superparamagnetic nanoparticles coated with various electric charges on &alpha;-synuclein and &beta;-amyloid proteins fibrillation process</p>

“…They have features such as paramagnetic superpower, high saturation field, nontoxicity, biodegradability, and variable loops. 9,10 Studies conducted on the effect of magnetically charged nanoparticles showed that the application of these nanoparticles as a carrier can be appropriate in treatment of many diseases. In addition, these nanoparticles, in fibrillation process, can have a crucial role in decreasing or delaying the plaque formation mechanism in A-proteins.…”