Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.

Reducing acetylated tau is neuroprotective in brain injury.

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.

Amyloid beta emerges from below the neck to disable the brain.

Accumulation of amyloid beta (Aß) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aß from the liver can promote brain pathology, supporting that peripheral Aß can contribute to neurodegeneration.

Restaurant kids' meal beverage offerings before and after implementation of healthy default beverage policy statewide in California compared with citywide in Wilmington, Delaware.

OBJECTIVE: In 2019, California and Wilmington, Delaware' implemented policies requiring healthier default beverages with restaurant kids' meals. The current study assessed restaurant beverage offerings and manager perceptions. DESIGN: Pre-post menu observations were conducted in California and Wilmington. Observations of cashiers/servers during orders were conducted pre-post implementation in California and post-implementation in Wilmington. Changes in California were compared using multilevel logistic regression and paired t tests. Post-implementation, managers were interviewed. SETTING: Inside and drive-through ordering venues in a sample of quick-service restaurants in low-income California communities and all restaurants in Wilmington subject to the policy, the month before and 7-12 months after policy implementation. PARTICIPANTS: Restaurant observations (California n 110; Wilmington n 14); managers (California n 75; Wilmington n 15). RESULTS: Pre-implementation, the most common kids' meal beverages on California menus were unflavoured milk and water (78·8 %, 52·0 %); in Wilmington, juice, milk and sugar-sweetened beverages were most common (81·8 %, 66·7 % and 46·2 %). Post-implementation, menus including only policy-consistent beverages significantly increased in California (9·7 % to 66·1 %, P < 0·0001), but remained constant in Wilmington (30·8 %). During orders, cashiers/servers offering only policy-consistent beverages significantly decreased post-implementation in California (5·0 % to 1·0 %, P = 0·002). Few managers (California 29·3 %; Wilmington 0 %) reported policy knowledge, although most expressed support. Most managers wanted additional information for customers and staff. CONCLUSIONS: While the proportion of menus offering only policy-consistent kids' meal default beverages increased in California, offerings did not change in Wilmington. In both jurisdictions, managers lacked policy knowledge, and few cashiers/servers offered only policy-consistent beverages. Additional efforts are needed to strengthen implementation of kids' meal beverage policies.

Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy.

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in Alzheimer's disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long-term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD.

Regulation of Tau Homeostasis and Toxicity by Acetylation.

Multiple neurodegenerative conditions including Alzheimer's disease and frontotemporal dementia are characterized by the accumulation of tau in the brain, associated with synapse loss and cognitive decline. Currently, the molecular events that lead to tau aggregation, and the pathological effects of the tau protein, are incompletely understood. Recent work has highlighted aberrant acetylation of tau as a key to understanding the pathophysiological roles of this protein. Specific acetylation sites regulate the formation of tau aggregates, synaptic signaling and long-term potentiation. Unraveling the details of this emerging story may offer novel insights into potential therapeutic approaches for devastating neurodegenerative diseases.

Acute knockdown of AMPA receptors reveals a trans-synaptic signal for presynaptic maturation.

Newly formed glutamatergic synapses often lack postsynaptic AMPA-type glutamate receptors (AMPARs). Aside from 'unsilencing' the postsynaptic site, however, the significance of postsynaptic AMPAR insertion during synapse maturation remains unclear. To investigate the role of AMPAR in synapse maturation, we used RNA interference (RNAi) to knockdown AMPARs in cultured hippocampal neurons. Surprisingly, loss of postsynaptic AMPARs increased the occurrence of presynaptically inactive synapses without changing the release probability of the remaining active synapses. Additionally, heterologous synapses formed between axons and AMPAR-expressing HEK cells develop significantly fewer inactive presynaptic terminals. The extracellular domain of the AMPAR subunit GluA2 was sufficient to reproduce this effect at heterologous synapses. Indeed, the retrograde signalling by AMPARs is independent of their channel function as RNAi-resistant AMPARs restore synaptic transmission in neurons lacking AMPARs despite chronic receptor antagonist treatment. Our findings suggest that postsynaptic AMPARs perform an organizational function at synapses that exceeds their standard role as ionotropic receptors by conveying a retrograde trans-synaptic signal that increases the transmission efficacy at a synapse.

Understanding benefits of a college student-homebound adult partnership program to support aging in place: An exploratory study.

The need for effective approaches to support aging and homebound adults is recognized internationally and domestically. This exploratory study sought to understand the proximal benefits of an intergenerational program in Delaware, USA that connected homebound individuals with college students. The primary goal was to describe program impacts on home-bound community residents to inform future research, program planning, and implementation. Outcomes of interest included quality of life, well-being, and independence. Semi-structured interviews were conducted with 19 participants recruited from a nonprofit partner. Findings yielded seven unique themes: emotional fulfillment, special feelings of support from a rare "unconditional" relationship, assistance with tasks, close connection with someone not ordinarily met, intergenerational understanding, someone to talk to, and appreciation. Additionally, the research team applied the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, to contextualize the approach and findings. Results inform future evaluation efforts of homebound visiting programs, which may seek to incorporate outcome indicators aligned with these themes and serve as a foundation for future quantitative measures of impact.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction.

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unfortunately, current treatment approaches for tauopathies have yielded limited success, underscoring the pressing need for novel therapeutic strategies. We observed distinct signatures of impaired glycogen metabolism in the Drosophila brain of the tauopathy model and the brain of AD patients, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen by activating glycogen phosphorylase (GlyP) ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC) derived neurons from FTD patients. We observed that glycogen breakdown redirects the glucose flux to the pentose phosphate pathway to alleviate oxidative stress. Our findings uncover a critical role for increased GlyP activity in mediating the neuroprotection benefit of dietary restriction (DR) through the cAMP-mediated protein kinase A (PKA) activation. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy treatment.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.

Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.

Understanding Impacts of SNAP Fruit and Vegetable Incentive Program at Farmers' Markets: Findings from a 13 State RCT.

Disparities in healthy food access and consumption are a major public health concern. This study reports the findings from a two-year randomized control trial conducted at 77 farmers' markets (FMs) in 13 states and the District of Columbia that sought to understand the impact of fruit and vegetable (FV) incentive vouchers, randomly issued at varied incentive levels to Supplemental Nutrition Assistance Program (SNAP) recipients, for use at FMs. Measures included FV and overall household food purchasing; FV consumption; food insecurity; health status; market expenditure; and demographics. A repeated-measures mixed-effects analysis and the Complier Average Causal Effect (CACE) were used to examine outcomes. Despite 82% reporting food insecurity in the prior year, the findings showed that financial incentives at FMs had statistically significant, positive effects on FV consumption; market expenditures increased with added incentives. SNAP recipients receiving an incentive of USD 0.40 for every USD 1.00 in SNAP spent an average of USD 19.03 per transaction, while those receiving USD 2 for every USD 1 (2:1) spent an average of USD 36.28 per transaction. The data showed that the incentive program at the highest level (2:1) maximally increased SNAP FM expenditure and FV consumption, increasing the latter by 0.31 daily cups among those who used their incentive (CACE model).

Between- and within-Group Differences in Fruit and Vegetable Purchases, Consumption, and BMI among Hispanic Farmers' Market Shoppers Who Use SNAP.

(1) Background: Despite considerable efforts to increase farmers' market access (FM) and improve household fruit and vegetable (FV) purchasing in low-income communities, little is known about the FV purchasing and consumption characteristics of low-income Hispanic farmers' market shoppers. (2) Methods: A secondary analysis of baseline data from a farmers' market study conducted between 2015 and 2017 (n = 2825) was performed. Participants who also received supplemental nutrition assistance program (SNAP) completed a 31-item online survey assessing demographics, health characteristics, and FV purchasing and consumption habits. Descriptive statistics and bivariate analyses were used to assess between- and within-group differences amongst Hispanic and non-Hispanic households. Regression analyses were used to examine associations among BMI, FV purchasing and consumption, and household size for Hispanic and non-Hispanic households as well as for Hispanic subgroups. (3) Results: The sample included 515 Hispanic and 2310 non-Hispanic SNAP-using FM shoppers in 13 states. Despite experiencing significantly higher food insecurity (89% vs. 81%, non-Hispanic), Hispanic shoppers consumed similar amounts of FV (3.04 cups/day) and spent less doing so. Significant subgroup differences were identified for FV purchasing. (4) Conclusions: Findings emphasize the importance of food insecurity and household size in FV interventions and underscore the capacity of Hispanic families to maintain FV consumption.

USDA Special Supplemental Nutrition Program for Women, Infants and Children (WIC) Vendor Criteria: An Examination of US Administrative Agency Variations.

The food retail environment has been directly linked to disparities in dietary behaviors and may in part explain racial and ethnic disparities in pregnancy-related deaths. The Special Supplemental Nutrition Program for Women, Infants and Children (WIC), administered by the United States Department of Agriculture, is associated with improved healthy food and beverage access due to its requirement for minimum stock of healthy foods and beverages in WIC-eligible stores. The selection and authorization criteria used to authorize WIC vendors varies widely from state to state with little known about the specific variations. This paper reviews and summarizes the differences across 16 of these criteria enacted by 89 WIC administrative agencies: the 50 states, the District of Columbia, five US Territories, and 33 Indian Tribal Organizations. Vendor selection and authorization criteria varied across WIC agencies without any consistent pattern. The wide variations in criteria and policies raise questions about the rational for inconsistency. Some of these variations, in combination, may result in reduced access to WIC-approved foods and beverages by WIC participants. For example, minimum square footage and/or number of cash register criteria may limit vendors to larger retail operations that are not typically located in high-risk, under-resourced communities where WIC vendors are most needed. Results highlight an opportunity to convene WIC stakeholders to review variations, their rationale, and implications thereof especially as this process could result in improved policies to ensure and improve healthy food and beverage access by WIC participants. More work remains to better understand the value of state WIC vendor authorization authority, particularly in states that have provided stronger monitoring requirements. This work might also examine if and how streamlining WIC vendor criteria (or at least certain components of them) across regional areas or across the country could provide an opportunity to advance interstate commerce and promote an equitable supply of food across the food system, while ensuring the protection for local, community-oriented WIC vendors.

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation.

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer's disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)­TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.

Astrocyte senescence promotes glutamate toxicity in cortical neurons.

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.

Healthy default beverage policies for kids' meals: A statewide baseline assessment of restaurant managers' perceptions and knowledge in Delaware.

The consumption of sugar-sweetened beverages (SSBs) has been linked to obesity, diabetes, and other negative health outcomes among children. In response, many government entities have enacted healthy default beverage policies that require restaurants offering bundled kids' meals-food and drink items combined and sold as a single unit-to include only healthier drinks. Despite growing interest in these policies, little is known about their potential reach, restaurant management perceptions, and possible implementation challenges. This study evaluated restaurant managers' knowledge and support of a policy in Delaware that had passed, but not yet gone into effect. We conducted structured in-person interviews with managers (n = 50) from full-service and quick-service chain and non-chain restaurants (QSRs) using a stratified random sample. Managers were interviewed about the number of bundled meals sold, beverage sales with those meals, and awareness and perceptions of the policy. On average, QSRs sold significantly more bundled kids' meals per week (281) compared to full-service restaurants (111), and managers from chain restaurants reported selling significantly more bundled kids' meals per week (233) compared to non-chain restaurants (91). Managers reported 72.5% of those meals were sold with a healthier beverage (water, milk, or 100% juice), consistent with the forthcoming policy, while 28% were sold with SSBs. Furthermore, although only three managers (6%) reported knowing about the policy, the majority supported it when it was explained. Our findings indicate general support for the intent of the policy, but suggest the need for tailored implementation approaches and additional education for restaurant manager's and staff.

Dynamics of postsynaptic glutamate receptor targeting.

Targeting of glutamate receptors to synapses is an important event in both developing and mature neurons. Glutamate receptors are delivered to nascent synapses during synaptogenesis and to existing synapses during activity-dependent synaptic strengthening. Increasing evidence suggests that glutamate receptors are inserted into the plasma membrane before they accumulate at the synapse. Lateral diffusion of receptors occurs at both synaptic and non-synaptic membranes, and glutamate receptors can exchange rapidly between synaptic and extrasynaptic sites. In addition, recent studies show that postsynaptic scaffold molecules can be highly mobile. The dynamic nature of the synapse suggests that many mechanisms might be involved in regulating synapse formation and synaptic plasticity.

The changing landscape of food deserts.

In this article, we discuss the most recent trends in food-retail access in low- and moderate-income communities in the United States of America. We begin with a review of the current literature on the number of people impacted by food deserts and then review several critical retail trends, including supercentres (such as Walmart), dollar stores, farmers markets and online food retail. We discuss the growing investment in incentive programmes, as well as new understandings of the impact of food deserts on health. In the United States of America, the number of communities without adequate access to healthy affordable food has declined, though more than 5.6 percent of the population still lives in low-access census tracts. At the same time, racial and economic disparities in food access remain a considerable concern, with around 30 percent more non-white residents facing limited access to food retail than white residents. We also provide recommendations for areas of future research.