Abstract: Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.

Abstract: OBJECTIVE: To describe and compare strategies adopted by overweight and obese low-income mothers living in different vulnerable contexts to deal with food constraints and feed their families. DESIGN: Qualitative in-depth interviews. Data were analyzed with exploratory content analysis and the number of segments per theme was used to compare neighborhoods. SETTING: Three low-income neighborhoods in Santos, Brazil. PARTICIPANTS: A purposive sample of 21 overweight or obese mothers. RESULTS: We identified three main types of strategies, namely, food acquisition, cooking, and eating. Food acquisition included social support and food-sourcing strategies. Social support strategies ranged from macro (governmental programs) to micro (family) levels. Food-sourcing strategies involved price research and use of credit to buy foods. Cooking approaches included optimizing food (e.g., adding water to beans), avoiding wastefulness, and substitutions (e.g., using water instead of milk when making cakes). Eating themes ranged from lack of quantity to lack of quality. Strategies to deal with the lack of food were affected by family dynamics, such as prioritizing provision of fruits to children. Food choices (e.g., low consumption of fruits and high consumption of fatty meats) derived from strategies may help promote overweight and obesity. Furthermore, for participants, financial constraints were perceived as barriers to following nutritionists' recommendations and weight loss. CONCLUSIONS: This study highlights the barriers that low-income women face in adopting a healthy diet and sheds light on the importance of the symbolic value of food, even in the context of food insecurity. Finally, it suggests that environmental aspects could increase the accessibility to fruits and vegetables. These findings could be used to inform the planning and implementation of interventions.