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Hormone-sensitive lipase (HSL) is the predominant lipase effector of catecholamine-stimulated lipolysis in adipocytes. HSL-dependent lipolysis in response to catecholamines is mediated by protein kinase A (PKA)-dependent phosphorylation of perilipin A (Peri A), an essential lipid droplet (LD)-associated protein. It is believed that perilipin phosphorylation is essential for the translocation of HSL from the cytosol to the LD, a key event in stimulated lipolysis. Using adipocytes retrovirally engineered from murine embryonic fibroblasts of periipin null mice (Pen-/- MEF), we demonstrate by cell fractionation and confocal microscopy that up to 50% of cellular HSL is LD-associated in the basal state and that PKA-stimulated HSL translocation is fully supported by adenoviral expression of a mutant perilipin lacking all six PKA sites (Peri AΔ1-6). PKA-stimulated HSL translocation was confirmed in differentiated brown adipocytes from perilipin null mice expressing an adipose-specific Peri AΔ1-6 transgene. Thus, PKA-induced HSL translocation was independent of perilipin phosphorylation. However, Peri AΔ1-6 failed to enhance PKA-stimulated lipolysis in either MEF adipocytes or differentiated brown adipocytes. Thus, the lipolytic action(s) of HSL at the LD surface requires PKA-dependent perilipin phosphorylation. In Peri-/- MEF adipocytes, PKA activation significantly enhanced the amount of HSL that could be cross-linked to and co-immunoprecipitated with ectopic Peri A. Notably, this enhanced cross-linking was blunted in Peri-/- MEF adipocytes expressing Peri AΔ1-6. This suggests that PKA-dependent perilipin phosphorylation facilitates (either direct or indirect) perilipin interaction with LD-associated HSL. These results redefine and expand our understanding of how perilipin regulates HSL-mediated lipolysis in adipocytes. [ABSTRACT FROM AUTHOR]

Previous studies have focused on the curative effects of memantine in patients with mild-to-moderate frontotemporal lobar degeneration (FTLD); however, its benefits in patients with moderate-to-severe FTLD have not been investigated. The present study explores the behavioral, cognitive and functional effects of memantine on behavioral variant frontotemporal dementia (bvFTD) in patients with mild and moderate-to-severe stage bvFTD. A total of 42 patients with bvFTD completed a 6-month treatment plan of 20 mg memantine daily in an open-label, self-controlled clinical trial. Patients were divided into two groups according to their Mini-Mental State Examination (MMSE) score: Mild (score, 21-26); and moderate-to-severe (score, 4-20). Primary endpoints included Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinic Dementia Rating (CDR) scores, and secondary endpoints comprised Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D), MMSE, Montreal Cognitive Assessment (MoCA), Activity of Daily Life (ADL) and Hamilton Depression Rating Scale (HAMD) scores. Memantine treatment had no effect on overall NPI-Q scores, with the exception of the agitation subdomain in all patients with bvFTD. However, patients with moderate-to-severe bvFTD exhibited a better performance than patients with mild bvFTD, demonstrated by improved NPI-Q total scores and subscales of agitation, depression, apathy and disinhibition. In the moderate-to-severe group, CDR and HAMD scores remained stable, but MMSE, MoCA and ADL scores were reduced after 6 months of treatment. Memantine was well-tolerated in patients. In conclusion, patients with moderate-to-severe bvFTD responded significantly better to memantine in comparison to patients with mild bvFTD with regard to their neuropsychiatric scores, while memantine did not present any cognitive or functional benefits in patients with mild bvFTD. A randomized, double-blind, placebo-controlled clinical trial with a larger number of patients is required to verify these promising results for patients with moderate-to-severe bvFTD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common neurodegenerative disorder with the earliest clinical symptom of olfactory dysfunction, which is a potential clinical marker for AD severity and progression. However, many questions remain unanswered. This article reviews relevant research on olfactory dysfunction in AD and evaluates the predictive value of olfactory dysfunction for the epidemiological, pathophysiological, and clinical features of AD, as well as for the conversion of cognitive impairment to AD. We summarize problems of existing studies and provide a useful reference for further studies in AD olfactory dysfunction and for clinical applications of olfactory testing. [ABSTRACT FROM AUTHOR]

Phosphorylation of the lipid droplet-associated protein perilipin A (Peri A) mediates the actions of cyclic AMP-dependent protein kinase A (PKA) to stimulate triglyceride hydrolysis (lipolysis) in adipocytes. Studies addressing how Peri A PKA sites regulate adipocyte lipolysis have relied on non-adipocyte cell models, which express neither adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triglyceride catabolism in mice, nor the ‘downstream’ lipase, hormone-sensitive lipase (HSL). ATGL and HSL are robustly expressed by adipocytes that we generated from murine embryonic fibroblasts of perilipin knock-out mice. Adenoviral expression of Peri A PKA site mutants in these cells reveals that mutation of serine 517 alone is sufficient to abrogate 95% of PKA (fonskolin)-stimulated fatty acid (FA) and glycerol release. Moreover, a ‘phosphomimetic’ (aspartic acid) substitution at serine 517 enhances PKA-stimulated FA release over levels obtained with wild type Pen A. Studies with ATGL-and HSL-directed small hairpin RNAs demonstrate that 1) ATGL activity is required for all PKA-stimulated FA and glycerol release in murine embryonic fibroblast adipocytes and 2) all PKA-stimulated FA release in the absence of HSL activity requires serine 517 phosphorylation. These results provide the first demonstration that Pen A regulates ATGL-dependent lipolysis and identify serine 517 as the Pen A PKA site essential for this regulation. The contributions of other PKA sites to PKA-stimulated lipolysis are manifested only in the presence of phosphonylated or phosphomimetic serine 517. [ABSTRACT FROM AUTHOR]