Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75 NTR ) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75 NTR may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.

Depression is a serious and widespread public health challenge. We examine the potential for leveraging social media postings as a new type of lens in understanding depression in populations. Information gleaned from social media bears potential to complement traditional survey techniques in its ability to provide finer grained measurements over time while radically expanding population sample sizes. We present work on using a crowdsourcing methodology to build a large corpus of postings on Twitter that have been shared by individuals diagnosed with clinical depression. Next, we develop a probabilistic model trained on this corpus to determine if posts could indicate depression. The model leverages signals of social activity, emotion, and language manifested on Twitter. Using the model, we introduce a social media depression index that may serve to characterize levels of depression in populations. Geographical, demographic and seasonal patterns of depression given by the measure confirm psychiatric findings and correlate highly with depression statistics reported by the Centers for Disease

Background Endocytic dysfunction and neurotrophin signaling deficits may underlie the selective vulnerability of hippocampal neurons during the progression of Alzheimer’s disease (AD), although there is little direct in vivo and biochemical evidence to support this hypothesis. Methods Microarray analysis of hippocampal CA1 pyramidal neurons acquired via laser capture microdissection (LCM) was performed using postmortem brain tissue. Validation was achieved using real-time quantitative PCR (qPCR) and immunoblot analysis. Mechanistic studies were performed using human fibroblasts subjected to overexpression with viral vectors or knockdown via siRNA. Results Expression levels of genes regulating early endosomes (rab5) and late endosomes (rab7) are selectively up regulated in homogeneous populations of CA1 neurons from individuals with mild cognitive impairment (MCI) and AD. The levels of these genes are selectively increased as antemortem measures of cognition decline during AD progression. Hippocampal qPCR and immunoblot analyses confirmed increased levels of these transcripts and their respective protein products. Elevation of select rab GTPases regulating endocytosis paralleled the down regulation of genes encoding the neurotrophin receptors TrkB and TrkC. Overexpression of rab5 in cells suppressed TrkB expression, whereas knockdown of TrkB expression did not alter rab5 levels, suggesting that TrkB down regulation is a consequence of endosomal dysfunction associated with elevated rab5 levels in early AD. Conclusions These data support the hypothesis that neuronal endosomal dysfunction is associated with preclinical AD. Increased endocytic pathway activity, driven by elevated rab GTPase expression, may result in long term deficits in hippocampal neurotrophic signaling and represent a key pathogenic mechanism underlying AD progression.

We consider social media as a promising tool for public health, focusing on the use of Twitter posts to build predictive models about the influence of childbirth on the forthcoming behavior and mood of new mothers. Using Twitter posts, we quantify postpartum changes in 376 mothers along dimensions of social engagement, emotion, social network, and linguistic style. We then construct statistical models from a training set of observations of these measures before and after the reported childbirth, to forecast significant postpartum changes in mothers. The predictive models can classify mothers who will change significantly following childbirth with an accuracy of 71%, using observations about their prenatal behavior, and as accurately as 80-83% when additionally leveraging the initial 2-3 weeks of postnatal data. The study is motivated by the opportunity to use social media to identify mothers at risk of postpartum depression, an underreported health concern among large populations, and to inform the design of low-cost, privacy-sensitive early-warning systems and intervention programs aimed at promoting wellness postpartum.

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A major feature of Alzheimer’s disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Reduced LC neuron numbers were also associated with increased postmortem neuropathology. To examine the cellular and molecular pathogenic processes underlying LC neurodegeneration in aMCI, we performed single population microarray analysis. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI. Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden. Taken together, these observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction. Moreover, they lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0411-2) contains supplementary material, which is available to authorized users.

The birth of a child is a major milestone in the life of parents. We leverage Facebook data shared voluntarily by 165 new mothers as streams of evidence for characterizing their postnatal experiences. We consider multiple measures including activity, social capital, emotion, and linguistic style in participants' Facebook data in pre-and postnatal periods. Our study includes detecting and predicting onset of post-partum depression (PPD). The work complements recent work on detecting and predicting significant postpartum changes in behavior, language, and affect from Twitter data. In contrast to prior studies, we gain access to ground truth on postpartum experiences via self-reports and a common psychometric instrument used to evaluate PPD. We develop a series of statistical models to predict, from data available before childbirth, a mother's likelihood of PPD. We corroborate our quantitative findings through interviews with mothers experiencing PPD. We find that increased social isolation and lowered availability of social capital on Facebook, are the best predictors of PPD in mothers.