Neuroregeneration in neurodegenerative disorders

Department of Cellular and Molecular Medicine, School of Medicine, 'Carol Davila' University of Medicine and Pharmacy, Bucharest 050474, Romania.
BMC Neurology (Impact Factor: 2.04). 06/2011; 11(1):75. DOI: 10.1186/1471-2377-11-75
Source: PubMed


Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration--implantation of viable cells as a therapeutical approach.
Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.
In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.

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    • "These symptoms are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is linked to a more than 80% loss of the level of dopamine in the striatum (Kirik et al., 1998). This fact has motivated researchers to reproduce the pathological features of PD in animal models in order to find therapeutic alternatives involving dopaminergic system restoration (Björklund, 2006; Kirik et al., 2006; Enciu et al., 2011). "
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    • "Moreover, it was shown that C57BL6 mice treated with Temozolomide (TMZ) to suppress adult hippocampal neurogenesis, displayed a delayed (or even absent) use of directed and place specific search patterns in the (reversal) MWM test compared to untreated mice, suggesting that hippocampal neurogenesis is necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning [67]. Although we did not observe a significant decrease in the amount of immature neurons in the 12-month-old AβPP-PS1 mice in our current study, reduced hippocampal neurogenesis has been found previously in AβPP-PS1 mice [69]–[71] and in AD patients [72], [73], and might underlie some aspects of the cognitive deficits in AD. "
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    ABSTRACT: Proton magnetic resonance spectroscopy ((1)H MRS) is a valuable tool in Alzheimer's disease research, investigating the functional integrity of the brain. The present longitudinal study set out to characterize the neurochemical profile of the hippocampus, measured by single voxel (1)H MRS at 7 Tesla, in the brains of AβPPSswe-PS1dE9 and wild-type mice at 8 and 12 months of age. Furthermore, we wanted to determine whether alterations in hippocampal metabolite levels coincided with behavioral changes, cognitive decline and neuropathological features, to gain a better understanding of the underlying neurodegenerative processes. Moreover, correlation analyses were performed in the 12-month-old AβPP-PS1 animals with the hippocampal amyloid-β deposition, TBS-T soluble Aβ levels and high-molecular weight Aβ aggregate levels to gain a better understanding of the possible involvement of Aβ in neurochemical and behavioral changes, cognitive decline and neuropathological features in AβPP-PS1 transgenic mice. Our results show that at 8 months of age AβPPswe-PS1dE9 mice display behavioral and cognitive changes compared to age-matched wild-type mice, as determined in the open field and the (reverse) Morris water maze. However, there were no variations in hippocampal metabolite levels at this age. AβPP-PS1 mice at 12 months of age display more severe behavioral and cognitive impairment, which coincided with alterations in hippocampal metabolite levels that suggest reduced neuronal integrity. Furthermore, correlation analyses suggest a possible role of Aβ in inflammatory processes, synaptic dysfunction and impaired neurogenesis.
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    • "Under a model such as that proposed by Rakyan et al. [3], and considering the two primary trends noted above, it could be speculated that the accumulation of methylation (typically associated with decreased gene expression) at bivalent loci in the aging brain could prevent neuronal cell regeneration. Thus, given that one of the primary pathologic features of age-related neurological disorders such as Alzheimer's disease and Parkinson's disease includes the loss of neuronal cell plasticity and cell death [20], [21], the relationship between the epigenetic alterations investigated in this study could have involvement in the onset or the progression of such disorders, and warrants further study. "
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    ABSTRACT: Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age-associated hyper-methylated sites in blood. In this study, we observed that age-associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00×10−5); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00×10−5). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders.
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