Neurodegeneration and Glial Activation Related CSF Biomarker as the Diagnosis of Alzheimer’s Disease: A Systematic Review and an Updated Meta-analysis

Objective: Recently, neuron specific enolase (NSE), Visinin-like protein-1 (VLP-1), neurogranin (Ng), and YKL-40 have been identified as candidates for neuronal degeneration and glial activation biomarkers. Therefore, we perform a comprehensive meta-analysis to assess the diagnostic value of CSF NSE, VLP-1, Ng and YKL-40 in Alzheimer’s disease (AD). Methods: We searched Pubmed, MEDLINE, EMBASE databases for research about the levels of CSF NSE, VLP-1, Ng and YKL-40 in AD patients compared with controls or other dementia diseases until Dec 2020. Results : The present meta-analysis contained a total of 51 studies comprising 6248 patients with dementia disorders and 3861 controls. Among them, there were 3262 patients with AD, 2456 patients with mild cognitive impairment (MCI), 173 patients with vascular dementia (VaD), 221 patients with frontotemporal dementia (FTD), and 136 with Lewy bodies dementia (DLB). Our study demonstrated that CSF NSE, VLP-1, Ng and YKL-40 levels were increased in AD as compared to healthy controls. We also observed that the CSF NSE level was higher in AD than VaD, suggesting CSF NSE might act as a key role in distinguishing between AD and VaD. Interestingly, there was a higher VLP-1 expression in AD, and a lower expression in DLB patients. Moreover, we found the CSF Ng level was increased in AD than MCI, implying CSF Ng might be a biomarker for identifying the progression of AD. Additionally, a significantly higher CSF YKL-40 level was detected not only in AD, but also in FTD, DLB, VaD, signifying YKL-40 was not sensitive in the diagnosis of AD. Conclusion: Our study confirmed that CSF levels of NSE, VLP-1, and Ng could be valuable biomarkers for identifying patients who are more susceptible to AD and distinguishing AD from other neurodegenerative dementia disorders.

Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles.Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras.This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

Dynamic Diversity of Glial Response Among Species in Spinal Cord Injury

The glial scar that forms after traumatic spinal cord injury (SCI) is mostly composed of microglia, NG2 glia, and astrocytes and plays dual roles in pathophysiological processes induced by the injury. On one hand, the glial scar acts as a chemical and physical obstacle to spontaneous axonal regeneration, thus preventing functional recovery, and, on the other hand, it partly limits lesion extension. The complex activation pattern of glial cells is associated with cellular and molecular crosstalk and interactions with immune cells. Interestingly, response to SCI is diverse among species: from amphibians and fishes that display rather limited (if any) glial scarring to mammals that exhibit a well-identifiable scar. Additionally, kinetics of glial activation varies among species. In rodents, microglia become activated before astrocytes, and both glial cell populations undergo activation processes reflected amongst others by proliferation and migration toward the injury site. In primates, glial cell activation is delayed as compared to rodents. Here, we compare the spatial and temporal diversity of the glial response, following SCI amongst species. A better understanding of mechanisms underlying glial activation and scar formation is a prerequisite to develop timely glial cell-specific therapeutic strategies that aim to increase functional recovery.

Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy

Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer’s disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid β (Aβ) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aβ42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aβ exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aβ deposits and helps to advance the understanding of geriatric TBI on the cellular level.

Neuroprotective Effect of Statins in a Rat Model of Chronic Ocular Hypertension

Glaucoma is an optic neuropathy in which the degeneration of retinal ganglion cells (RGCs) results in irreversible vison loss. Therefore, neuroprotection of RGCs from glaucomatous afflictions is crucial for glaucoma treatment. In this study, we aimed to investigate the beneficial effects of statins in the protection of RGCs using a rat model. Glaucomatous injury was induced in rats by chronic ocular hypertension (OHT) achieved after performing a circumlimbal suture. The rats were given either statins such as simvastatin and atorvastatin or a solvent weekly for 6 weeks. Retina sections underwent hematoxylin and eosin, Brn3a, or cleaved casepase-3 staining to evaluate RGC survival. In addition, modulation of glial activation was assessed. While the retinas without statin treatment exhibited increased RGC death due to chronic OHT, statins promoted the survival of RGCs and reduced apoptosis. Statins also suppressed chronic OHT-mediated glial activation in the retina. Our results demonstrate that statins exert neuroprotective effects in rat retinas exposed to chronic OHT, which may support the prospect of statins being a glaucoma treatment.