Discussion intense in later stages of AD 71.


BMI1 belongs to the PcG family of proteins,
which maintain gene repression through epigenetic chromatin modifications. They
play a critical role in cell proliferation and differentiation but they are
equally essential in regulation of oxidative stress. It was found that Bmi1 expression
progressively declines in old neurons and this leads to down-regulation of AOR
and therefore to increase of oxidative damages. To the best of our knowledge,
this study is the first to describe the levels of BMI1 protein in serum and CSF
from AD patients compared to healthy individuals.

Although latest researches were shown that in
neurodegenerative condition the expression of Bmi1 decreased, our results
showed that BMI1 levels in blood serum and CSF of AD patients were increased
compared with the control group.

The theory of neuroapoptosis in Alzheimer’s
Disease had supporters and critics. Colurso et al. have supported that that
neuronal apoptosis occurs in AD 60, while some years later, this has been
disputed by Woodhouse et al., who report no apoptotic morphology in AD cases
64. Finally, scientific community agrees on that excitotoxicity occurs in AD
70, suggested that this phenomenon is more intense in later stages of AD
71. Specifically, Olney et al. have shown that the accumulation of ?-amyloid leads to excitotoxicity
induced by excessive activation of NMDA receptors and results to
neurodegeneration 69. It has shown that neuronal necrosis is the result of a
reactions cascade that begins with hyperactivation of NMDA receptors. The following
excessive calcium influx stimulate the activation of calpains and ERK1/2. In
the next step ERK1/2 stimulated MSK1/2 and observed increased levels of MSK1/2
induced- H3S28ph. In turn, H3S28ph could displace the PRC1 from chromatin
results to neuronal necrosis through Trx activation (fig). The next question
was if the displacement of PRC1 from chromatin or the degradation of complex
resulted to necrosis. Kai Liua et al. attempted to answer this question and
they arrived at the observation that the protein levels of Bmi1, the core
component of PRC1, were not altered but the intensity of Bmi-1was reduced in
the nucleus suggesting that, in fact, the Bmi-1 only displaces from chromatin
and is not degradated. These findings offer an explanation of observed rising
levels of Bmi1 and other relative proteins in biological fluids. For this
reason, we hypothesize that, these increased levels of Bmi1 and other proteins
in biological fluids, may be the result of neuronal necrosis which occur in MCI
and AD patients.

Bmi1 as Potential Biomarker for AD

Most of the time Alzheimer’s disease (AD) can
be diagnosed accurately with careful clinical history, cognitive testing,
neurological examination, and structural brain MRI. However, there are certain
circumstances wherein detection of specific biomarkers of neurodegeneration or
underlying AD pathology will impact the clinical diagnosis or treatment plan.

Bmi1 as Potential Therapeutic Targets for
Neuronal Necrosis

As known, the excitotoxicity which promoted
from NMDA receptors hyperactivation is a principal cause of neuronal necrosis
in many neurodegenerative diseases including Alzheimer’s Disease 43. For this
reason, the first attempts of drug design targeted in the NMDA receptors
blocking, however the use of antagonists of NMDA receptors have not been
accepting due to their side effects 44. The most common methodology to reduce
the side effects of a drug is to design a new one to target in a downstream
partner of a pathway. Recent studies suggest that the target of JIL-1/PRC1/Trx
cascade may constitutes a promising aspect due to several advantages .  The PCR1 may introduce the ideal target because
studies demonstrated that PRC1 act neuroprotective since loss of PRC1 promoted
neuronal necrosis.


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