Expression of Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Neurotrophin-3 mRNAs in Human Cortical Xenografts

Trophic factors play an important role in the development of neurons and glia. In order to study the involvement of neurotrophins in human cortical development, human fetal parietal cortical tissue, obtained after early elective abortions, was transplanted to cortical cavities in immunosuppressed rats. Using in situ hybridization it was demonstrated that nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNAs are expressed in developing human cortical xenografts. We conclude that neurotrophins may play a role in human cortical development and rat-derived astroglial cells could be involved in establishing reciprocal “permissive sites”

Female Sprague Dawley Rats Show Impaired Spatial Memory in the 8-Arm Radial Maze under Dim Blue and Red Light

Light intensity and wavelength strongly influence mood and cognition in humans and rodent animal models. The aim of the present study was to explore if dim white (7.6–17.7 lux) , blue (1.3–2.3 lux), and red light (0.8–1.4 lux) affect spatial memory of male and female Sprague Dawley rats in the 8-arm radial maze. Our data show that spatial memory significantly improved within 5 daily learning sessions (each 5 trials) under dim white light, which was not different between male and female rats. However, dim blue and red light significantly reduced spatial learning of female rats in the 8-arm radial maze in the last training session (session 5). In conclusion, we suggest that female Sprague Dawley rats show reduced learning under blue and red light

Two Blood Monocytic Biomarkers (CCL15 and p21) Combined with the Mini-Mental State Examination Discriminate Alzheimer's Disease Patients from Healthy Subjects

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. In AD, monocytes migrate across the blood-brain barrier and differentiate into microglia, are linked to inflammatory responses and display age-dependent decreases in telomere lengths. Methods: Six monocyte-specific chemokines and the (telomere-associated) tumor suppressor proteins p53 and p21 were determined by multiplex immunoassay in plasma and monocyte extracts of patients with AD or mild cognitive impairment, and levels were compared between patients and controls (without cognitive impairment). Results: CCL15 (macrophage inflammatory protein-1δ), CXCL9 (monokine-induced by interferon-γ) and p21 levels were decreased in monocytes of AD patients compared with controls. Conclusion: The combination of monocytic CCL15 and p21 together with the Mini-Mental State Examination enables to differentiate AD patients from controls with high specificity and sensitivity

L-type calcium channel blockers and substance P induce angiogenesis of cortical vessels associated with beta-amyloid plaques in an Alzheimer mouse model

AbstractIt is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using 35S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis

Biomaterial based strategies to reconstruct the nigrostriatal pathway in organotypic slice co-cultures

Protection or repair of the nigrostriatal pathway represents a principal disease-modifying therapeutic strategy for Parkinson's disease (PD). Glial cell line-derived neurotrophic factor (GDNF) holds great therapeutic potential for PD, but its efficacious delivery remains difficult. The aim of this study was to evaluate the potential of different biomaterials (hydrogels, microspheres, cryogels and microcontact printed surfaces) for reconstructing the nigrostriatal pathway in organotypic co-culture of ventral mesencephalon and dorsal striatum. The biomaterials (either alone or loaded with GDNF) were locally applied onto the brain co-slices and fiber growth between the co-slices was evaluated after three weeks in culture based on staining for tyrosine hydroxylase (TH). Collagen hydrogels loaded with GDNF slightly promoted the TH+ nerve fiber growth towards the dorsal striatum, while GDNF loaded microspheres embedded within the hydrogels did not provide an improvement. Cryogels alone or loaded with GDNF also enhanced TH+ fiber growth. Lines of GDNF immobilized onto the membrane inserts via microcontact printing also significantly improved TH+ fiber growth. In conclusion, this study shows that various biomaterials and tissue engineering techniques can be employed to regenerate the nigrostriatal pathway in organotypic brain slices. This comparison of techniques highlights the relative merits of different technologies that researchers can use/develop for neuronal regeneration strategies

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

Multiple system atrophy (MSA) is a progressive late onset neurodegenerative α-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of α-synuclein (αSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar αSYN and dysfunction of the ubiquitin–proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial αSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human αSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic αSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic αSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic αSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human αSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA