Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.

Highlights d Ab and tau work together to cause behavioral and transcriptional deficits in mice d In mice with Ab and tau, glial gene expression increases and synaptic genes decrease d Tau is present in synaptic terminals in APP/PS1+Tau mice and human Alzheimer brain d In mice, lowering tau levels improves cognition and restores gene expression

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD) and several theories have been advanced to explain the relationship. A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble aggregates that impair synaptic and network activity. Here, we used the most disease-relevant form of Aβ, protein isolated from AD brain. Using this material, we show that the synaptotoxic effects of Aβ depend on expression of APP and that the Aβ-mediated impairment of synaptic plasticity is accompanied by presynaptic effects that disrupt the excitatory/inhibitory (E/I) balance. The net increase in the E/I ratio and inhibition of plasticity are associated with Aβ localizing to synapses and binding of soluble Aβ aggregates to synapses requires the expression of APP. Our findings indicate a role for APP in AD pathogenesis beyond the generation of Aβ and suggest modulation of APP expression as a therapy for AD.SIGNIFICANCE STATEMENTHere, we report on the plasticity-disrupting effects of amyloid β-protein (Aβ) isolated from Alzheimer's disease (AD) brain and the requirement of amyloid precursor protein (APP) for these effects. We show that Aβ-containing AD brain extracts block hippocampal LTP, augment glutamate release probability, and disrupt the excitatory/inhibitory balance. These effects are associated with Aβ localizing to synapses and genetic ablation of APP prevents both Aβ binding and Aβ-mediated synaptic dysfunctions. Our results emphasize the importance of APP in AD and should stimulate new studies to elucidate APP-related targets suitable for pharmacological manipulation.

To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a ‘chemical harpoon’. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.DOI: http://dx.doi.org/10.7554/eLife.06638.001

Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently observed that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), is associated with exacerbated synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. We examined brain tissue from 33 subjects (7-10 per group). We pooled tissue from all subjects in each group for unbiased proteomic analyses followed by validation with individual case samples. Our analysis identified over 5500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.

Despite more than a century of research, the aetiology of sporadic Alzheimer's disease ( AD ) remains unclear and finding disease modifying treatments for AD presents one of the biggest medical challenges of our time. AD pathology is characterized by deposits of aggregated amyloid beta (Aβ) in amyloid plaques and aggregated tau in neurofibrillary tangles. These aggregates begin in distinct brain regions and spread throughout the brain in stereotypical patterns. Neurodegeneration, comprising loss of synapses and neurons, occurs in brain regions with high tangle pathology, and an inflammatory response of glial cells appears in brain regions with pathological aggregates. Inheriting an apolipoprotein E ε4 ( APOE 4 ) allele strongly increases the risk of developing AD for reasons that are not yet entirely clear. Substantial amounts of evidence support a role for APOE in modulating the aggregation and clearance of Aβ, and data have been accumulating recently implicating APOE 4 in exacerbating neurodegeneration, tau pathology and inflammation. We hypothesize that APOE 4 influences all the pathological hallmarks of AD and may sit at the interface between neurodegeneration, inflammation and the spread of pathologies through the brain. Here, we conducted a systematic search of the literature and review evidence supporting a role for APOE 4 in neurodegeneration and inflammation. While there is no direct evidence yet for APOE 4 influencing the spread of pathology, we postulate that this may be found in future based on the literature reviewed here. In conclusion, this review highlights the importance of understanding the role of APOE in multiple important pathological mechanisms in AD .

Human-to-human transmission of Creutzfeldt–Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aβ) protein associated with Alzheimer’s disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aβ seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aβ and give insights into the possibility of iatrogenic transmission of AD and CAA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1703-0) contains supplementary material, which is available to authorized users.

There is limited information on the behavioural and physiological responses of sheep to the components of road transport. Behavioural observations and physiological measurements of ‘stress’, injury and dehydration were made on weaned lambs (35 kg) before, during and after either stationary confinement or transport for 22 h at four space allowances (0·22, 0·27, 0·31 and 0·41 m2 per sheep). Two groups were not loaded (a control group with access to food and water, and a group with no food and no water for 12 h). During the confinement and transport period, the proportion of scans spent lying and the proportion of scans spent ruminating was significantly less than that before treatment (P < 0·01). After 3 h of transport, the proportion of scans spent lying was significantly less at the 0·22 m2 per sheep space allowance than at the other space allowances. The proportion of scans spent lying down was only significantly greater during confinement compared with transport at the 0·22 m2 per sheep space allowance and during the first 6 h at the 0·31 m2 per sheep space allowance. During transport, the heart rate and plasma cortisol concentration were greater than during stationary confinement (P < 0·05), indicating that some aspect of the journey was acting as a stressor. During transport the frequency of losses of balance and the frequency of slips was less at the 0·22 m2 per sheep space allowance than at the 0·27 and 0·41 m2 per sheep space allowances. However, there was no effect of space allowance on either plasma cortisol concentration or biochemical measures of injury. The median frequency of potentially traumatic events during transport was <5 per h and there was little evidence to suggest that increasing space allowance increased the risk of traumatic injury. During the first 12 h after treatment, the proportion of scans spent eating was greater and the proportion of scans spent lying were less than those spent before treatment (P < 0·001). Post-treatment, water intake and packed cell volume were greater in transported sheep than in control sheep (P < 0·05). However, there was no significant effect of 12 h without water on total plasma protein concentration and plasma vasopressin concentration (P > 0·05). Under the conditions of this study, sheep with a live weight of 35 kg can be transported for 12 h at space allowances of between 0·22 and 0·41 m2 per sheep without showing major physiological changes indicative of injury and dehydration. However, the sheep appeared to be hungry after 12 h without food and showed a cortisol and heart rate response to transport, indicating that some aspect of transport was acting as a stressor. A space allowance of 0·22 m2 per sheep cannot be recommended for 35 kg sheep as there is insufficient space for most of the sheep to lie down during transport. Whereas a space allowance of at least 0·27 m2 per sheep does allow most sheep sufficient space to lie down.