Biology subjects

Santana, R. A.

Publications and source records attributed to Santana, R. A..

3 recordsLinked to original sources

bioRxiv2025

AD-genes and Aging Increase Count and Size of Lipid Droplets, Accompanied by Accumulation of Neutral Lipids Across Compartments in Hippocampal Neurons.

Lipid homeostasis plays a crucial role in neuronal function, yet its dynamics during aging and neurodegenerative diseases remain poorly understood. Our study unveils critical age-related changes in lipid polarity and lipid droplet characteristics in hippocampal neurons from non-transgenic (NTg) mice and from an Alzheimers disease-model (3xTg-AD). Using advanced spectral imaging and phasor analysis techniques, we tracked lipid polarity with Nile Red in vitro across various cellular compartments and quantified lipid droplet features. We discovered that NTg neurons exhibit a progressive increase in global lipid polarity from young to middle age, followed by a slight decrease in old age. This pattern suggests that neurons actively regulate their lipid composition throughout the lifespan, potentially in response to changing cellular needs. In contrast, AD-like (or 3xTg-AD) neurons fail to show this age-related increase in lipid polarity, instead displaying a consistent reduction in lipid polarity across all ages. Lipid droplet analysis revealed a transient accumulation of larger droplets in middle-aged NTg neurons, while AD-transgenic neurons showed early and persistent increases in lipid droplet size and number. Principal component analysis uncovered coordinated changes in lipid polarity and droplet characteristics, highlighting distinct patterns of lipid partitioning in NTg and AD-affected neurons. These findings suggest that AD-associated genetic modifications disrupt normal age-related adaptations in lipid metabolism and organization. Our results provide new insights into the complex interplay between lipid homeostasis, aging, and AD-genotypic stress. Understanding these dynamics may open new avenues for developing therapeutic strategies to maintain neuronal health and potentially slow AD progression.

biophysics↗

bioRxiv2025

Treatment of age-related decreases in GTP levels restores endocytosis and autophagy

Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimers model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal A{beta} aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.

neuroscience↗

bioRxiv2022

The genome of the brackish-water malaria vector Anopheles aquasalis

Anopheles aquasalis is a primary malaria vector in coastal South America that grows in brackish waters of mangroves. Its importance has increased in recent years as it has been established as a model for parasite-vector studies for non-model Plasmodium species, such as P. yoelli. In this study, we present the complete genome of An. aquasalis and offer some insights into evolution and physiology. With a 162Mb and 12,446 coding proteins, the An. aquasalis genome is similar in size and gene content as other neotropical anophelines. 1,038 single-copy orthologs are present in An. aquasalis and all Diptera and it was possible to infer that An. aquasalis diverged from An. darlingi (the main malaria vector in inland South America) nearly 14 million years ago (mya). Ion transport and metabolism proteins is one the major gene families in An. aquasalis with 660 genes. Amongst these genes, important gene families relevant for osmosis control (e.g., aquaporins, vacuolar-ATPases, Na+/K+-ATPases and carbonic anhydrases) were identified in one-to-one orthologs with other anophelines. Evolutionary analysis suggests that all osmotic regulation genes are under strong purifying selection. We also observed low copy number variation in immunity-related genes (for which all classical pathways were described) and insecticide resistance genes. This is the third genome of a neotropical anopheline published so far. The data provided by this study may offer candidate genes for further studies on parasite-vector interactions and for studies on how brackish water anophelines deals with high fluctuation in water salinity. Significance StatementThe brackish water mosquito Anopheles aquasalis is a primary malaria vector in coastal South America. Besides its peculiar ecological features (it is one of the few anopheline mosquitoes that survives high fluctuation of water salinity), An. aquasalis has gained relevance in recent years as a model for parasite-vector studies for non-model Plasmodium parasites. Still, the physiology and genetics of An. aquasalis are poorly understood. Here we present the genome of An. aquasalis with more than 12,000 annotated genes, offering insights in genome evolution, osmoregulation related, immunity, chemosensory and insecticide resistance genes. The data presented here will help to further advance the studies on An. aquasalis genetics and physiology to better understand parasite-vector interactions in non-model organisms.

genomics↗