NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy

Alzheimer’s disease (AD) is a devastating neurodegenerative disease causing irreversible cognitive decline in the elderly. There is no disease-modifying therapy for this condition and the mechanisms underpinning neuronal dysfunction and neurodegeneration are unclear. Compromised cytoskeletal integrity within neurons is reported in AD. This is believed to result from loss-of-function of the microtubule-associated protein tau, which becomes hyper-phosphorylated and deposits into neurofibrillary tangles in AD. We have developed a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterised by microtubule destabilisation, axonal transport disruption, synaptic defects and behavioural impairments. Here we show that a microtubule-stabilising drug, NAPVSIPQ (NAP), prevents as well as reverses these phenotypes even after they have become established. Moreover, it does not alter abnormal tau levels indicating that it by-passes toxic tau altogether. Thus, microtubule stabilisation is a disease-modifying therapeutic strategy protecting against tau-mediated neuronal dysfunction, which holds great promise for tauopathies like AD

Auditory temporal acuity improves with age in the male mouse auditory thalamus: A role for perineuronal nets?

The ability to perceive and interpret environmental sound accurately is conserved across many species and is fundamental for understanding communication via vocalizations. Auditory acuity and temporally controlled neuronal firing underpin this ability. Deterioration in neuronal firing precision likely contributes to poorer hearing performance, yet the role of neural processing by key nuclei in the central auditory pathways is not fully understood. Here, we record from the auditory thalamus (medial geniculate body [MGB]) of young and middle‐aged, normally hearing male CBA/Ca mice. We report changes in temporal processing of auditory stimuli, with neurons recorded from ventral and medial MGB subdivisions of older animals more likely to synchronize to rapid temporally varying stimuli. MGB subdivisions also showed increased probability of neuronal firing and shorter response latencies to clicks in older animals. Histological investigation of neuronal extracellular specializations, perineuronal nets (PNNs) and axonal coats, in the MGB identified greater organization of PNNs around MGB neurons and the presence of axonal coats within older animals. This supports the observation that neural responses recorded from ventral and medial MGB of older mice were more likely to synchronize to temporally varying stimuli presented at faster repetition rates than those recorded from young adult animals. These changes are observed in animals with normal hearing thresholds, confirming that neural processing differs between the MGB subdivisions and such processing is associated with age‐related changes to PNNs. Understanding these age‐related changes and how they occur have important implications for the design of effective therapeutic interventions to improve speech intelligibility into later life

Far-field Unlabelled Super-Resolution Imaging with Superoscillatory Illumination

Unlabelled super-resolution is the next grand challenge in imaging. Stimulated emission depletion and single-molecule microscopies have revolutionised the life sciences but are still limited by the need for reporters (labels) embedded within the sample. While the Veselago-Pendry “super-lens” using a negative-index metamaterial is a promising idea for imaging beyond the diffraction limit, there are substantial technological challenges to its realisation. Another route to far-field subwavelength focusing is using optical superoscillations: engineered interference of multiple coherent waves creating an, in principle, arbitrarily small hotspot. Here we demonstrate microscopy with superoscillatory illumination of the object and describe its underlying principles. We show that far-field images taken with superoscillatory illumination are themselves superoscillatory and hence can reveal fine structural details of the object that are lost in conventional far-field imaging. We show that the resolution of a superoscillatory microscope is determined by the size of the hotspot, rather than the bandwidth of the optical instrument. We demonstrate high-frame-rate polarisation-contrast imaging of unmodified living cells with resolution significantly exceeding that achievable with conventional instruments. This non-algorithmic, low-phototoxicity imaging technology is a powerful tool both for biological research and for super-resolution imaging of samples that do not allow labelling, such as the interior of silicon chips

Analysis of Chaperone mRNA Expression in the Adult Mouse Brain by Meta Analysis of the Allen Brain Atlas

The pathology of many neurodegenerative diseases is characterized by the accumulation of misfolded and aggregated proteins in various cell types and regional substructures throughout the central and peripheral nervous systems. The accumulation of these aggregated proteins signals dysfunction of cellular protein homeostatic mechanisms such as the ubiquitin/proteasome system, autophagy, and the chaperone network. Although there are several published studies in which transcriptional profiling has been used to examine gene expression in various tissues, including tissues of neurodegenerative disease models, there has not been a report that focuses exclusively on expression of the chaperone network. In the present study, we used the Allen Brain Atlas online database to analyze chaperone expression levels. This database utilizes a quantitative in situ hybridization approach and provides data on 270 chaperone genes within many substructures of the adult mouse brain. We determined that 256 of these chaperone genes are expressed at some level. Surprisingly, relatively few genes, only 30, showed significant variations in levels of mRNA across different substructures of the brain. The greatest degree of variability was exhibited by genes of the DnaJ co-chaperone, Tetratricopeptide repeat, and the HSPH families. Our analysis provides a valuable resource towards determining how variations in chaperone gene expression may modulate the vulnerability of specific neuronal populations of mammalian brain

Expression of the small heat shock protein family in the mouse CNS: differential anatomical and biochemical compartmentalization

The small heat shock proteins (sHsps) are a family of molecular chaperones defined by an alpha-crystallin domain that is important for sHsps oligomerization and chaperone activity. sHsps perform many physiological functions including the maintenance of the cellular cytoskeleton, the regulation of protein aggregation and modulate cell survival in a number of cell types including glial and neuronal cells. Many of these functions have been implicated in disease processes in the CNS and indeed sHsps are considered targets for disease therapy. Despite this, there is no study that systematically and comparatively characterized sHsps expression in the CNS. In the present study we have analyzed the expression of this gene family in the mouse brain by reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization and Western blotting. Gene expression analysis of the 10 known members of mammalian sHsps confirms the presence of 5 sHsps in the CNS. A distinct white matter specific expression pattern for HspB5 and overlapping expression of HspB1 and HspB8 in the lateral and dorsal ventricles of the brain is observed. We confirm protein expression of HspB1, HspB5, HspB6 and HspB8 in the brain. Further subcellular fractionation of brain and synaptosomes details a distinct subcompartment-specific association and detergent solubility of sHsps. This biochemical signature is indicative of an association with synaptic and other neural specializations. This observation will help one understand the functional role played by sHsps during physiology and pathology in the CNS

Glial cell changes in the central auditory system through the lifespan of rhesus macaques – a potential mechanism for inflammation in the progression of age-related hearing loss

Age-related hearing loss (ARHL) is a common condition, affecting half of adults over the age of 75. It has a large impact on quality of life, contributing to social isolation and depression. Despite ARHL being common, it is not universal, suggesting that its progression may be amenable to modulation or therapy - this would allow a level of hearing adequate for social interaction to be maintained for longer. Pathology in the cochlea is the main focus of current presbycusis (ARHL) research. Due to a loss of input from the cochlea, there is also degeneration of the central auditory system, which causes auditory processing to be impaired. An association between raised inflammatory status and decreased hearing ability has been shown in an aging human population. It is feasible that systemic inflammation could be contributing to hearing loss by increasing degeneration of the central auditory pathway. During aging there are changes to the immune system, including a tendency towards chronic low grade inflammation.The link between systemic inflammation and neurodegenerative diseases is well established. Given that there is also neurodegeneration occurring in ARHL, it is possible that hearing loss progression could be intensified by systemic inflammation via interaction with the glia. Perineuronal nets (PNN) are specialised extracellular matrix structures and have an important role in the auditory system as they aid intregration of sound inputs. Therefore, alongside glial changes, an alteration in PNN structure could contribute to hearing impairment. The rhesus macaque is an important model in understanding a possible role for inflammation in ARHL: similar to humans, non-human primates have an unusually long lifespan compared to mammals of a similar size, they develop chronic inflammation with age and they variably develop ARHL