The mature optic nerve cannot regenerate when injured, leaving victims of traumatic nerve damage or diseases such as glaucoma with irreversible visual losses. Recent studies have identified ways to stimulate retinal ganglion cells to regenerate axons part-way through the optic nerve, but it remains unknown whether mature axons can reenter the brain, navigate to appropriate target areas, or restore vision. We show here that with adequate stimulation, retinal ganglion cells are able to regenerate axons the full length of the visual pathway and on into the lateral geniculate nucleus, superior colliculus, and other visual centers. Regeneration partially restores the optomotor response, depth perception, and circadian photoentrainment, demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-␤ (A␤) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble A␤ oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, A␤ oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where A␤ oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with A␤ oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links A␤ oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity.

Background Degeneration of the locus ceruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer’s disease. Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect Aβ toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knock-out mice with APP/PS1 mice, overexpressing mutant amyloid precursor protein and presenilin-1. DBH (−/−) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation (LTP), and synaptic protein levels were assessed. Results The modest impairments in spatial memory and hippocampal LTP displayed by young APP/PS1 or DBH(−/−) single mutant mice were augmented in DBH(−/−)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total Ca2+/calmodulin-dependent protein kinases II (CaMKII) and N-Methyl-D-aspartate receptor 2A (NR2A), increased N-Methyl-D-aspartate receptor 2B (NR2B) levels and were independent of Aβ accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-DOPS. Conclusions These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of CaMKII and N-Methyl-D-aspartate receptors, and suggest that NA supplementation could be beneficial in early AD.

Among the numerous ways of assessing regeneration after peripheral nerve lesions, the analysis of gait is one of the most important, because it shows the recovery of function, which is the ultimate goal of the repair machinery. The sciatic function index was introduced as a method to assess reinnervation after an experimental sciatic nerve lesion, and was adapted to the mouse model. The sciatic static index (SSI), is more simple and practical to perform, and is not so influenced by gait's velocity, but this method has not yet been adapted to the mouse model of sciatic lesion. We used 63 male Swiss mice (Mus musculus) to develop a formula to the sciatic static index in mice (SSIm). The animals were divided on three groups (control, transection and crush). They were evaluated at the preoperative and 7th, 14th, 21st, 28th, 35th and 42nd days postoperative by the ink track method (SFI), and by the acquisition of photographs of the plantar aspects of the injured and uninjured hind paws. The parameters evaluated were the 1-5 toe spread (TS), the 2-4 toe spread (ITS) and the distance between the tip of the third toe and the most posterior aspect of the paw (PL), on both methods. After verifying the temporal pattern of function, correlation and reproducibility of the measurements, we performed a multiple regression analysis using SFI values as dependent variable, and the TS, ITS and PL measured with the photo method as independent variables, and found the formula of the SSI for mice (SSIm). The three groups (control, transection and crush) had a characteristic pattern of dysfunction. The parameters measured in the ink and photo method had variable but significant correlations between them (P<0.000), but photo method of measurement showed a better reproducibility. The correlation between SFI and SSIm showed a high correlation coefficient (r=0.892, P<0.000), and demonstrates that SSIm can be used as an alternative method to assess the functional status relative of sciatic nerve activity in mice.

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(Ϫ/Ϫ) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(Ϫ/Ϫ) mice, whereas APP/PS1 or Ear2(Ϫ/Ϫ) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(Ϫ/Ϫ) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of ␤-CaMKII and spatial memory performance in APP/PS1 Ear2(Ϫ/Ϫ) mice. These changes were not accompanied by altered APP processing or amyloid ␤ peptide (A␤) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A␤ and suggests that NA supplementation could be beneficial in treating AD.

Protein aggregation and amyloid accumulation in different tissues are associated with cellular dysfunction and toxicity in important human pathologies, including Alzheimer's disease and various forms of systemic amyloidosis. Soluble oligomers formed at the early stages of protein aggregation have been increasingly recognized as the main toxic species in amyloid diseases. To gain insight into the mechanisms of toxicity instigated by soluble protein oligomers, we have investigated the aggregation of hen egg white lysozyme (HEWL), a normally harmless protein. HEWL initially aggregates into b-sheet rich, roughly spherical oligomers which appear to convert with time into protofibrils and mature amyloid fibrils. HEWL oligomers are potently neurotoxic to rat cortical neurons in culture, while mature amyloid fibrils are little or non-toxic. Interestingly, when added to cortical neuronal cultures HEWL oligomers induce tau hyperphosphorylation at epitopes that are characteristically phosphorylated in neurons exposed to soluble oligomers of the amyloid-b peptide. Furthermore, injection of HEWL oligomers in the cerebral cortices of adult rats induces extensive neurodegeneration in different brain areas. These results show that soluble oligomers from a non-disease related protein can mimic specific neuronal pathologies thought to be induced by soluble amyloid-b peptide oligomers in Alzheimer's disease and support the notion that amyloid oligomers from different proteins may share common structural determinants that would explain their generic cytotoxicities. Keywords: amyloid oligomers, cerebral cortex, hen egg white lysozyme, hippocampus, neurotoxicity, tau phosphorylation. It has become clear in recent years that amyloid protein aggregates play crucial roles in important human pathologies, including Alzheimer's disease (AD), various forms of systemic amyloidosis and other disorders (Kelly 2000;Stefani and Dobson 2003;Ferreira et al. 2007). Despite the lack of sequence homology between distinct disease-related amyloid-forming proteins and peptides, the process of aggregation appears to be similar in all cases and the resulting materials share common tinctorial and morphological characteristics (Dobson 1999). In addition, recent studies have shown that the ability to form amyloid aggregates in vitro is not an exclusive property of proteins and peptides associated with disease but rather seems to be an intrinsic characteristic of polypeptide chains (e.g. Guijarro et al. 1998;Bouchard et al. 2000;Fandrich et al. 2001;Pertinhez et al. 2001;De Felice et al. 2004a).Human lysozyme variants have been implicated in autosomal hereditary systemic amyloidosis (Pepys et al. 1993;Valleix et al. 2002;Yazaki et al. 2003). Single amino acid mutations in lysozyme have been shown to lead to structural destabilization of the variants and to an increased propensity to form amyloid aggregates (Booth et al. 1997 Abbreviations used: AD, Alzheimer's disease; Ab, amyloid-beta peptide; Ab42, amyloid beta peptide 1-42; DAPI, 4¢,6-diamidino-2-p...