Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.

Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.

Alzheimer's disease-related dysregulation of mRNA translation causes key pathological features with ageing.

Alzheimer's disease (AD) is characterised by Aß and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aß increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aß accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.

Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.

This corrects the article DOI: 10.1038/ncomms15132.

Native prion protein homodimers are destabilized by oligomeric amyloid ß 1-42 species as shown by single-molecule imaging.

Prion proteins (PrPc) are receptors for amyloid ß 1-42 (Aß1-42) oligomers, but we do not know the impact of Aß1-42 binding to PrPc on the interaction of membrane-bound PrPc with molecules that regulate downstream biological pathways. Stability of the PrPc dimeric complex and subsequent intermolecular interactions with membranous or cytoplasmic molecules are important for physiological functions of PrPc including neuroprotection. The principal aim of this study was to determine whether homodimer lifetime of PrPc is affected by the presence of Aß1-42 oligomers. Single-molecule imaging analysis was carried out by total internal reflection fluorescence microscopy in PrPc-transfected CHO-K1 cells in the absence or presence of characterized Aß1-42 oligomers. The contribution of different Aß1-42 oligomer conformations to Alzheimer's disease pathophysiology and to the associated neurotoxicity is unknown. To be precise, with the oligomeric species used in our study, we biochemically analyzed the molecular weight of oligomers formed from Aß1-42 monomers under our experimental conditions. The lifetime of PrPc homodimers was 210 ms, and in the presence of Aß1-42 oligomers, the lifetime was significantly reduced (to 92 ms). The reduction of PrPc homodimer lifetime by Aß1-42 oligomers may impair PrPc-mediated downstream neuroprotective signaling.

Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.

The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.

Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease synapse loss precedes neuronal loss and correlates best with impaired memory formation. However, the mechanisms underlying synaptic degeneration in Alzheimer's disease are not well known. Further, it is unclear why synapses in AD cerebellum are protected from degeneration. Our recent work on the cyclin-dependent kinase 5 activator p25 suggested that expression of the multifunctional presynaptic molecule cysteine string protein alpha (CSPalpha) may be affected in Alzheimer's disease. RESULTS: Using western blots and immunohistochemistry, we found that CSPalpha expression is reduced in hippocampus and superior temporal gyrus in Alzheimer's disease. Reduced CSPalpha expression occurred before synaptophysin levels drop, suggesting that it contributes to the initial stages of synaptic degeneration. Surprisingly, we also found that CSPalpha expression is upregulated in cerebellum in Alzheimer's disease. This CSPalpha upregulation reached the same level as in young, healthy cerebellum. We tested the idea whether CSPalpha upregulation might be neuroprotective, using htau mice, a model of tauopathy that expresses the entire wild-type human tau gene in the absence of mouse tau. In htau mice CSPalpha expression was found to be elevated at times when neuronal loss did not occur. CONCLUSION: Our findings provide evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease. In the forebrain CSPalpha expression is reduced early in the disease and this may contribute to the initial stages of synaptic degeneration. In the cerebellum CSPalpha expression is upregulated to young, healthy levels and this may protect cerebellar synapses and neurons to survive. Accordingly, CSPalpha upregulation also occurs in a mouse model of tauopathy only at time when neuronal loss does not take place.