Proteomic alterations in the cerebellum and hippocampus in an Alzheimer's disease mouse model: Alleviating effect of palmatine.

Alzheimer's disease (AD) is one of the most prevalent diseases that lead to memory deficiencies, severe behavioral abnormalities, and ultimately death. The need for more appropriate treatment of AD continues, and remains a sought-after goal. Previous studies showed palmatine (PAL), an isoquinoline alkaloid, might have the potential for combating AD because of its in vitro and in vivo activities. In this study, we aimed to assess PAL's therapeutic potential and gain insights into the working mechanism on protein level in the AD mouse model brain, for the first time. To this end, PAL was administered to 12-month-old 5xFAD mice at two doses after its successful isolation from the Siberian barberry shrub. PAL (10 mg/kg) showed statistically significant improvement in the memory and learning phase on the Morris water maze test. The PAL's ability to pass through the blood-brain barrier was verified via Multiple Reaction Monitoring (MRM). Label-free proteomics analysis revealed PAL administration led to changes most prominently in the cerebellum, followed by the hippocampus, but none in the cortex. Most of the differentially expressed proteins in PAL compared to the 5xFAD control group (ALZ) were the opposite of those in ALZ in comparison to healthy Alzheimer's littermates (ALM) group. HS105, HS12A, and RL12 were detected as hub proteins in the cerebellum. Collectively, here we present PAL as a potential therapeutic candidate owing to its alleviating effect in 5xFAD mice on not only cognitive impairment but also proteomes in the cerebellum and hippocampus.

Evaluation of the Therapeutic Effect of Lycoramine on Alzheimer's Disease in Mouse Model.

BACKGROUND: Alzheimer's disease is one of the leading health problems characterized by the accumulation of Aß and hyperphosphorylated tau that account for the senile plaque formations causing extensive cognitive decline. Many of the clinical diagnoses of Alzheimer's disease are made in the late stages, when the pathological changes have already progressed. OBJECTIVE: The objective of this study is to evaluate the promising therapeutic effects of a natural compound, lycoramine, which has been shown to have therapeutic potential in several studies and to understand its mechanism of action on the molecular level via differential protein expression analyses. METHODS: Lycoramine and galantamine, an FDA approved drug used in the treatment of mild to moderate AD, were administered to 12 month-old 5xFAD mice. Effects of the compounds were investigated by Morris water maze, immunohistochemistry and label- free differential protein expression analyses. RESULTS: Here we demonstrated the reversal of cognitive decline via behavioral testing and the clearance of Aß plaques. Proteomics analysis provided in-depth information on the statistically significant protein perturbations in the cortex, hippocampus and cerebellum sections to hypothesize the possible clearance mechanisms of the plaque formation and the molecular mechanism of the reversal of cognitive decline in a transgenic mouse model. Bioinformatics analyses showed altered molecular pathways that can be linked with the reversal of cognitive decline observed after lycoramine administration but not with galantamine. CONCLUSION: Lycoramine shows therapeutic potential to halt and reverse cognitive decline at the late stages of disease progression, and holds great promise for the treatment of Alzheimer's disease.

Glutaric acidemia type II patient with thalassemia minor and novel electron transfer flavoprotein-A gene mutations: A case report and review of literature.

Glutaric acidemia type II (GAII), also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAII with novel electron transfer flavoprotein (ETF)-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, riboflavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor development was normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.