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


METHODS
Here 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.


RESULTS
Stabilization 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.


CONCLUSIONS
These 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.
Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel. sterned@mail.biu.ac.il.
Micaela
M
Glat
Hadas
H
Skaat
Noa
N
Menkes-Caspi
Shlomo
S
Margel
Edward A
EA
Stern
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D005290:Ferric Compounds / Q000737:chemistry*; D005337:Fibrin / Q000737:chemistry; D006801:Humans; D055767:Immobilized Proteins; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012720:Severity of Illness Index; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D005290:Ferric Compounds; D055767:Immobilized Proteins; C558298:Mapt protein, mouse; D010455:Peptides; D016875:tau Proteins; C000499:ferric oxide; D005337:Fibrin