Artificial intelligence for neurodegenerative experimental models.

INTRODUCTION: Experimental models are essential tools in neurodegenerative disease research. However, the translation of insights and drugs discovered in model systems has proven immensely challenging, marred by high failure rates in human clinical trials. METHODS: Here we review the application of artificial intelligence (AI) and machine learning (ML) in experimental medicine for dementia research. RESULTS: Considering the specific challenges of reproducibility and translation between other species or model systems and human biology in preclinical dementia research, we highlight best practices and resources that can be leveraged to quantify and evaluate translatability. We then evaluate how AI and ML approaches could be applied to enhance both cross-model reproducibility and translation to human biology, while sustaining biological interpretability. DISCUSSION: AI and ML approaches in experimental medicine remain in their infancy. However, they have great potential to strengthen preclinical research and translation if based upon adequate, robust, and reproducible experimental data. HIGHLIGHTS: There are increasing applications of AI in experimental medicine. We identified issues in reproducibility, cross-species translation, and data curation in the field. Our review highlights data resources and AI approaches as solutions. Multi-omics analysis with AI offers exciting future possibilities in drug discovery.

Microglia produce the amyloidogenic ABri peptide in familial British dementia.

Mutations in ITM2B cause familial British, Danish, Chinese and Korean dementias. In familial British dementia (FBD) a mutation in the stop codon of the ITM2B gene (also known as BRI2 ) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer's disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons, and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. Consequently, the ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. Pathological examination of post-mortem tissue support ABri expression in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are the major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. This has implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer's disease.

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.

Surface modified nanoliposome formulations provide sustained release for 5-FU and increase cytotoxicity on A431 cell line.

Malignant melanoma is a type of skin cancer with high risk of metastasis. 5-Fluorouracil is commonly used for treatment of skin cancer, however its penetration through the skin is found to be insufficient in some cases. Therefore, we optimized its pharmacokinetics by fabricating 5- Fluorouracil-loaded nanoliposome formulations modified with Poly-L-lysine coating. 5-Fluorouracil-loaded nanoliposome formulations were prepared using dipalmitoylphosphatidylcholine, dicethylphosphate and cholesterol having encapsulation efficiency of 45 ± 9.61%. The particle size, zeta potential, polydispersity index and encapsulation rate of the prepared formulation was found to be 237.9 ± 0.986 nm, 41.4 ± 1.060 mV, 0.233 ± 0.019 and 88.2 ± 7.85%, respectively. Surface characterization, molecular structure and thermal property illumination of the formulations were performed alongside stability studies. The In-vitro release of 5-FU from Lipo-FU6 and PLL-1 formulations was investigated by dialysis membrane method. Within the first 12 hours, the percentage release of 5-FU from Lipo-FU6 and PLL-1 formulations was observed to be 47.17% and 20.84%, respectively. Moreover, the cytotoxicity study on A431 epidermal carcinoma cell lines has revealed that 5-FU-loaded formulations were toxic to cells unlike the 5-FU free formulations. In conclusion, PLL coated nanoliposome formulations showed a potential to be an effective option for further combined drug/gene therapy applications.

Liposome-based combination therapy for acne treatment.

Acne vulgaris is one of the most common chronic diseases worldwide with the high prevalence ratio of about 80-85% in patients who are in puberty period. For the treatment options, many conventional dosage forms are available; however, existing limitations of systemic administration of drugs (oral antibiotics), such as adverse events and resistance, led for seek of new formulation options. In this study, liposomes containing tetracycline HCl and tretinoin were prepared by the film formation method. In vitro characterization studies revealed that liposomes (111.10 ± 8.02 nm; P.D.I.=0.198 ± 0.03; Z.P.=25.83 ± 0.40 mV) with an encapsulation efficiency more than 80% for both APIs were formulated. In order to maintain a suitable viscosity for topical application, optimized liposomal formulations were dispersed in carbopol-based gel. In vitro release of APIs was sustained for 24 hours with released amounts of 56.44% and 58.44% for tetracycline HCl and tretinoin, respectively. Stability evaluation of both liposomes and liposomes in hydrogels was investigated for 6 months at 4 °C and 25 °C; and no statistically significant change was observed in terms of particle size, zeta potential, encapsulation efficiency, appearance, pH, and viscosity. Cytotoxicity tests confirmed the nontoxic structure of liposomal gel formulations on mice fibroblast cells. In addition, antibacterial efficacy has been proven with Staphylococcus aureus and Streptococcus epidermidis strains as well as the effect on biofilm formation and eradication. As a result, we hereby presented a new combination drug product, which consists of dual active ingredients having comedolytic and bacteriostatic effects in a single, safe, and stable liposome formulation.