In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.
Background:
CA1 subregion of the hippocampal formation is one of the primarily affected
structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this
region.
Objective:
In this study, we aimed to identify the protein expression alterations throughout the
pre-pathological, progression and pathological stages of AD mouse model.
Method:
The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from
transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 wereβmonths of age. Morris
water maze test and immunohistochemistry staining of A performed to determine the stages of the disease
in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics
analysis.
Results:
A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of
mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance.
Pathway analysis based on the unique and common proteins within the groups revealed that
several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid
metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in
ROS production via diminished SOD level and impairment of neuronal integrity.
Conclusion:
We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration
may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer’s
disease.
Biomimetic nanomaterials bearing natural bioactive signals which are derived from extracellular matrix components like laminin and heparan sulfates provide promising therapeutic strategies for regeneration of the nervous system. However, no research has been reported exploring the use of biomimetic materials against degeneration in Parkinson's disease. In this work, we investigated potential therapeutic effects of heparan sulfate and laminin mimetic PA nanofibers on reduction of striatal injury in experimental Parkinson's disease model. PA nanofibers enhanced functional recovery associated with enhanced striatal dopamine and tyrosine hydroxylase content as well as reduced cleaved-Caspase-3 levels. Overall, this study shows the improvement in consequences of Parkinsonism in rats and provides a new platform for treatment of Parkinson's disease.
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