Neuronal loss and microgliosis are restricted to the core of Aß deposits in mouse models of Alzheimer's disease.

Amyloid-ß (Aß) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aß deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aß deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aß deposits, mouse models of AD, which develop abundant Aß deposits in the aged brain without pathologic tau, were used to examine the co-localization of NeuN-positive neurons, NF-H-positive axons, MBP-positive myelin sheaths, and Aß deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA-1-positive microglia, was significantly increased in the core area of cerebral Aß deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aß deposits was correlated with Aß deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aß deposits, and this restricted loss probably occurs because the Aß deposit attracts microglia, which cluster in the core area where Aß toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aß deposits in the absence of pathologic tau.

Protective effect of BMSCs-derived exosomes mediated by BDNF on TBI via miR-216a-5p.

BACKGROUND Transplantation of exosomes derived from mesenchymal stem cells (MSCs-Exo) can improve the recovery of neurological function in rats after traumatic brain injury (TBI). We tested a new hypothesis that BDNF-mediated MSCs-Exo could effectively promote functional recovery and neurogenesis of rats after TBI. MATERIAL AND METHOD BMSCs of rats were extracted by whole bone marrow culture, BDNF was added to BMSCs for intervention, supernatant was collected, and exosomes were separated and purified by hypercentrifugation. Exosomes were identified by WB, TEM and particle size analysis and subsequently used in cell and animal experiments. We investigated the recovery of sensorimotor function and spatial learning ability, inflammation inhibition and neuron regeneration in rats after TBI. RESULTS Compared with group MSCs-Exo, group BDNF-mediated MSCs-Exo showed better effects in promoting the recovery of sensorimotor function and spatial learning ability. BDNF-mediated MSCs-Exo successfully inhibited inflammation and promoted neuronal regeneration in vivo and in vitro. We further analyzed miRNA in BDNF-mediated MSCs-Exo and MSCs-Exo, and found that the expression of miR-216a-5p in BDNF-mediated MSCs-Exo was significantly higher than that in MSCs-Exo by qRT-PCR. Rescue experiment indicated that miR-216a-5p has a similar function to BDNF-mediated MSCs-Exo. CONCLUSIONS In conclusion, we found that BDNF-mediated MSCs-Exo can better promote neurogenesis and inhibit apoptosis than MSCs-Exo in rats after TBI, and the mechanism may be related to the high expression of miR-216a-5p.

Three-dimensional bioprinting collagen/silk fibroin scaffold combined with neural stem cells promotes nerve regeneration after spinal cord injury.

Many studies have shown that bio-scaffolds have important value for promoting axonal regeneration of injured spinal cord. Indeed, cell transplantation and bio-scaffold implantation are considered to be effective methods for neural regeneration. This study was designed to fabricate a type of three-dimensional collagen/silk fibroin scaffold (3D-CF) with cavities that simulate the anatomy of normal spinal cord. This scaffold allows cell growth in vitro and in vivo. To observe the effects of combined transplantation of neural stem cells (NSCs) and 3D-CF on the repair of spinal cord injury. Forty Sprague-Dawley rats were divided into four groups: sham (only laminectomy was performed), spinal cord injury (transection injury of T10 spinal cord without any transplantation), 3D-CF (3D scaffold was transplanted into the local injured cavity), and 3D-CF + NSCs (3D scaffold co-cultured with NSCs was transplanted into the local injured cavity. Neuroelectrophysiology, imaging, hematoxylin-eosin staining, argentaffin staining, immunofluorescence staining, and western blot assay were performed. Apart from the sham group, neurological scores were significantly higher in the 3D-CF + NSCs group compared with other groups. Moreover, latency of the 3D-CF + NSCs group was significantly reduced, while the amplitude was significantly increased in motor evoked potential tests. The results of magnetic resonance imaging and diffusion tensor imaging showed that both spinal cord continuity and the filling of injury cavity were the best in the 3D-CF + NSCs group. Moreover, regenerative axons were abundant and glial scarring was reduced in the 3D-CF + NSCs group compared with other groups. These results confirm that implantation of 3D-CF combined with NSCs can promote the repair of injured spinal cord. This study was approved by the Institutional Animal Care and Use Committee of People's Armed Police Force Medical Center in 2017 (approval No. 2017-0007.2).

Brains of rhesus monkeys display Aß deposits and glial pathology while lacking Aß dimers and other Alzheimer's pathologies.

Cerebral amyloid beta (Aß) deposits are the main early pathology of Alzheimer's disease (AD). However, abundant Aß deposits also occur spontaneously in the brains of many healthy people who are free of AD with advancing aging. A crucial unanswered question in AD prevention is why AD does not develop in some elderly people, despite the presence of Aß deposits. The answer may lie in the composition of Aß oligomer isoforms in the Aß deposits of healthy brains, which are different from AD brains. However, which Aß oligomer triggers the transformation from aging to AD pathogenesis is still under debate. Some researchers insist that the Aß 12-mer causes AD pathology, while others suggest that the Aß dimer is the crucial molecule in AD pathology. Aged rhesus monkeys spontaneously develop Aß deposits in the brain with striking similarities to those of aged humans. Thus, rhesus monkeys are an ideal natural model to study the composition of Aß oligomer isoforms and their downstream effects on AD pathology. In this study, we found that Aß deposits in aged monkey brains included 3-mer, 5-mer, 9-mer, 10-mer, and 12-mer oligomers, but not 2-mer oligomers. The Aß deposits, which were devoid of Aß dimers, induced glial pathology (microgliosis, abnormal microglia morphology, and astrocytosis), but not the subsequent downstream pathologies of AD, including Tau pathology, neurodegeneration, and synapse loss. Our results indicate that the Aß dimer plays an important role in AD pathogenesis. Thus, targeting the Aß dimer is a promising strategy for preventing AD.

Amyloid-ß Derived from the Brain of the Alzheimer's Disease Transgenic Mouse Is Resistant to Proteolytic Digestion Due to Its Conformation.

The main pathological feature of Alzheimer's disease (AD) is the formation of abundant amyloid-ß (Aß) plaques in the human brain. Studies have reported that Aß from the AD brain is resistant to proteolytic digestion, which may explain why Aß cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Aß derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Aß peptide, whose amino acid sequence was identical to that of AD mouse-derived Aß but whose conformation was different (i.e., the native protein, but not the peptide, folded into a three-dimensional conformation). To address this question, we denatured AD mouse-derived Aß with urea and found that Aß became proteinase K-sensitive. This phenomenon was concentration-dependent, and these results were confirmed by another protein denaturant, guanidinium hydrochloride. We recovered the conformation of the denatured AD mouse-derived Aß by eliminating urea and adding the human Aß peptide, and we found that human Aß was converted to the proteinase K-resistant form in the presence of partially undenatured AD mouse-derived Aß. However, upon the addition of the rat Aß peptide, there were no Aß proteinase K-resistant fragments. Our results show that the resistance of AD mouse-derived Aß to proteolytic digestion is dependent on the three-dimensional conformation of Aß. In summary, this study provides new insights on why Aß plaques fail to be degraded in the human brain.

Upregulation of Aß42 in the Brain and Bodily Fluids of Rhesus Monkeys with Aging.

The cerebral accumulation of amyloid beta (Aß) is one of the key pathological hallmarks of Alzheimer's disease (AD). Aß is also found in bodily fluids such as the cerebrospinal fluid (CSF) and plasma. However, the significance of Aß accumulation in the brain and different bodily pools, as well as its correlation with aging and cerebral amyloid pathology, is not completely understood. To better understand this question, we selected the rhesus monkey, which is phylogenetically and physiologically highly similar to the human, as a model to study. We quantified the levels of the two main Aß isoforms (Aß42 and Aß40) in different sections of the brain (frontal cortex, temporal cortex, and hippocampus) and bodily fluids (CSF and plasma) of rhesus monkeys at different developmental phases (young, 5-9 years of age; mature, 10-19 years of age; and old, 21-24 years of age). We found that the levels of neuronal and insoluble Aß42 increased significantly in the brain with aging, suggesting that this specific isoform might be directly involved in aging and AD-like pathophysiology. There was no significant change in the Aß40 level in the brain with aging. In addition, the Aß42 level, but not the Aß40 level, in both the CSF and plasma increased with aging. We also identified a positive correlation between Aß42 in the CSF and plasma and Aß42 in the brain. Taken collectively, our results indicate that there is an association between Aß accumulation and age. These results support the increased incidence of AD with aging.