ASN NEURO最新文献

The levels of brain-derived neurotrophic factor (BDNF) in the corpus callosum have previously been shown to have a critical impact on oligodendrocyte (OLG) lineage cells during cuprizone-elicited demyelination. In particular, BDNF+/- mice exhibit greater losses in myelin protein levels compared to wild-type mice after cuprizone. To investigate whether OLGs may directly mediate these effects of BDNF during a lesion in vivo, we used the cuprizone model of demyelination with inducible conditional male knockout mice to specifically delete the high-affinity tropomyosin receptor kinase B (TrkB) receptor from proteolipid protein + OLGs during cuprizone-elicited demyelination and subsequent remyelination. The loss of TrkB during cuprizone-elicited demyelination results in an increased sensitivity to demyelination as demonstrated by greater deficits in myelin protein levels, greater decreases in numbers of mature OLGs, increased numbers of demyelinated axons, and decreased myelin thickness. When mice are removed from cuprizone, they exhibit a delayed recovery in myelin proteins and myelin. Our data indicate that following a demyelinating lesion, TrkB in OLGs positively regulates myelin protein expression, myelin itself, and remyelination.

Background: Frontotemporal lobar degeneration (FTLD) is the third most common dementing neurodegenerative disease with nearly 80% having no known etiology.

Objective: Growing evidence that neurodegeneration can be linked to dysregulated metabolism prompted us to measure a panel of trophic factors, receptors, and molecules that modulate brain metabolic function in FTLD.

Methods: Postmortem frontal (Brodmann's area [BA]8/9 and BA24) and temporal (BA38) lobe homogenates were used to measure immunoreactivity to Tau, phosphorylated tau (pTau), ubiquitin, 4-hydroxynonenal (HNE), transforming growth factor-beta 1 (TGF-β1) and its receptor (TGF-β1R), brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, tropomyosin receptor kinase, and insulin and insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2) and their receptors by direct-binding enzyme-linked immunosorbent assay.

Results: FTLD brains had significantly elevated pTau, ubiquitin, TGF-β1, and HNE immunoreactivity relative to control. In addition, BDNF and neurotrophin-4 were respectively reduced in BA8/9 and BA38, while neurotrophin-3 and nerve growth factor were upregulated in BA38, and tropomyosin receptor kinase was elevated in BA24. Lastly, insulin and insulin receptor expressions were elevated in the frontal lobe, IGF-1 was increased in BA24, IGF-1R was upregulated in all three brain regions, and IGF-2 receptor was reduced in BA24 and BA38.

Conclusions: Aberrantly increased levels of pTau, ubiquitin, HNE, and TGF-β1, marking neurodegeneration, oxidative stress, and neuroinflammation, overlap with altered expression of insulin/IGF signaling ligand and receptors in frontal and temporal lobe regions targeted by FTLD. Dysregulation of insulin-IGF signaling networks could account for brain hypometabolism and several characteristic neuropathologic features that characterize FTLD but overlap with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Body Disease.

Mild traumatic brain injury (mTBI) in children is a common and serious public health problem. Traditional neuroimaging findings in children who sustain mTBI are often normal, putting them at risk for repeated mTBI (rmTBI). There is a need for more sensitive imaging techniques capable of detecting subtle neurophysiological alterations after injury. We examined neurochemical and white matter changes using diffusion tensor imaging of the whole brain and proton magnetic resonance spectroscopy of the hippocampi at 7 Tesla in 18-day-old male rats at 7 days after mTBI and rmTBI. Traumatic axonal injury was assessed by beta-amyloid precursor protein accumulation using immunohistochemistry. A significant decrease in fractional anisotropy and increase in axial and radial diffusivity were observed in several brain regions, especially in white matter regions, after a single mTBI versus sham and more prominently after rmTBI. In addition, we observed accumulation of beta-amyloid precursor protein in the external capsule after mTBI and rmTBI. mTBI and rmTBI reduced the N-acetylaspartate/creatine ratio (NAA/Cr) and increased the myoinositol/creatine ratio (Ins/Cr) versus sham. rmTBI exacerbated the reduction in NAA/Cr versus mTBI. The choline/creatine (Cho/Cr) and (lipid/Macro Molecule 1)/creatine (Lip/Cr) ratios were also decreased after rmTBI versus sham. Diffusion tensor imaging findings along with the decrease in Cho and Lip after rmTBI may reflect damage to axonal membrane. NAA and Ins are altered at 7 days after mTBI and rmTBI likely reflecting neuro-axonal damage and glial response, respectively. These findings may be relevant to understanding the extent of disability following mTBI and rmTBI in the immature brain and may identify possible therapeutic targets.