Biology subjects

Tallino, S.

Publications and source records attributed to Tallino, S..

4 recordsLinked to original sources

bioRxiv2026

Dyrk1a inhibition with the Novel Compound DYR533: A Cross-Disease Therapeutic Strategy Targeting Amyloidosis, Tau Pathogenesis, and Neuroinflammation

Alzheimers disease (AD) and related dementias are rapidly increasing in prevalence, yet disease-modifying therapies remain largely focused on amyloid-{beta} (A{beta}) with limited efficacy against tau pathology and neuroinflammation--key drivers of neurodegeneration and clinical decline. Dual-specificity tyrosine-phosphorylation-regulated kinase 1a (Dyrk1a) phosphorylates tau and amyloid precursor protein and regulates inflammatory signaling, positioning it as a convergence point across pathogenic pathways. We show that brain Dyrk1a protein levels are consistently elevated across ADRDs, replicating findings in AD, confirming prior observations in Picks disease, and demonstrating dysregulation in corticobasal degeneration and progressive supranuclear palsy. We developed DYR533, a selective, orally bioavailable, brain-penetrant Type 1 Dyrk1a kinase inhibitor that also inhibits autophosphorylation and reduces kinase abundance. Across three mouse models (3xTg-AD, PS19, Ts65Dn), DYR533 reduced pathological tau hyperphosphorylation, attenuated neuroinflammation, ameliorated amyloidosis, and improved anxiety-like behavior and spatial memory, collectively supporting Dyrk1a inhibition and DYR533 as a therapeutic strategy for ADRD.

neuroscience↗

bioRxiv2025

Sex-Specific Links Between Low Choline, Metabolic Dysfunction, andNeuropathology in Obesity: Insights from Humans and the 3xTg-AD MouseModel of Alzheimer's disease.

The growing prevalence of obesity, a risk factor for disorders such as Alzheimers Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (A{beta}) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, [~]90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5-24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. HighlightsO_LIObesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimers disease (AD). C_LIO_LIWomen exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. C_LIO_LILower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. C_LIO_LI3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants. C_LI

pathology↗

bioRxiv2024

Adult choline supplementation in a Down syndrome model reduces co-morbidities and improves cognition

Down syndrome (DS) is the most common cause of early-onset Alzheimers disease (AD). Dietary choline has been proposed as a modifiable factor to improve cognitive and pathological outcomes of AD, especially as many do not reach adequate daily intake levels. Perinatal choline supplementation (Ch+) in the Ts65Dn mouse model of DS protects offspring against AD-relevant pathology and improves cognition, and dietary Ch+ in adult AD models also ameliorates pathology and improves cognition. However, dietary Ch+ in adult Ts65Dn mice has not yet been explored. To test whether Ch+ in adulthood improves DS co-morbidities, we fed trisomic Ts65Dn mice and disomic littermate controls with either choline normal (ChN; 1.1 g/kg) or Ch+ (5 g/kg) diets from 4.5-14 months of age. We found that Ch+ improved cognitive flexibility in a reverse place preference task and reduced weight gain and peripheral inflammation in female mice, whereas Ch+ improved glucose metabolism in male mice. In conclusion, we found that adulthood Ch+ benefits behavioral and biological factors important for general well-being in DS and related to AD risk.

neuroscience↗

bioRxiv2022

Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimers disease hallmarks

Evidence suggests that environmental factors may contribute to Alzheimers disease (AD). The B-like vitamin choline plays key roles in body- and brain-related functions. Choline produced endogenously by the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. [~]90% of Americans dont reach the recommended daily choline intake. Thus, its imperative to determine whether dietary deficiency increases disease outcomes. Here, we placed 3xTg-AD, a model of AD, and non-transgenic (NonTg) control mice on either a sufficient choline (ChN) or choline deficient (Ch-; choline deficiency) diet from 3 to 12 (early to late adulthood) months of age. Ch- reduced plasma choline and acetylcholine levels, increased weight, and impaired both glucose metabolism and motor function in NonTg, with 3xTg-AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, and elevated Amyloid-{beta} and phosphorylated tau in the hippocampus and cortex of 3xTg-AD Ch- mice. Unbiased proteomic analyses revealed Ch- altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, Ch- altered protein networks associated with insulin metabolism, mitochondrial function, and inflammation. Collectively, our data highlight that dietary choline intake is necessary to prevent systems-wide organ pathology and reduce AD hallmark pathologies.

neuroscience↗