Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aß42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

HLA-DR5 and DQB1*03 class II alleles are associated with cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) may present with eczematous lesions, mycosis fungoides (MF), or as exfoliative erythroderma with circulating atypical cells, Sezary syndrome (SS). The "malignant" T cells are epidermotropic and clonal, but whether they respond to antigen stimulation is unknown. Because CD4+ lymphocytes recognize antigen presented by histocompatibility locus antigen (HLA) class II molecules, and HLA association have been found in autoimmune skin diseases, we determined by allele-specific oligonucleotide typing whether HLA-DR or DQ alleles were associated with CTCL and its two variants MF (n = 47) and SS (n = 23). Phenotypic frequencies were compared by chi-square and Fisher exact test, and p values were corrected independently for either 12 DR or 15 DQ alleles. HLA-DR5, previously associated with MF, was significantly increased in all 70 CTCL patients (31.5%) versus controls (11%) (uncorrected p value [Pnc] = 0.000038, odds ratio [OR] = 3.9, 1.9 < OR < 8.1), in MF patients (34%) (Pnc = 0.000047, OR = 3.62, 1.9 < OR < 10), and in SS patients (26%) (Pnc = 0.03, OR = 3, 0.9 < OR < 9.3). HLA-DQB1*03 alleles (0301, 0302, and 0303) were increased in 72% of all CTCL patients versus 49% of controls (corrected p value [Pc] = 0.014, OR = 2.7, 1.4 < OR < 5.1), in SS (82%) (Pc = 0.05, OR = 4.7, 1.4 < OR < 5), and in MF (67%) (Pnc = 0.024, OR = 2.15, 1 < OR < 4.5). DQB1*0502 was strongly increased in SS patients (Pc = 0.045, OR = 7.75, 1.25 < OR < 48). Although HLA-DQB1*0603 and HLA-DR6 (1301, 1302, and 1402) were decreased in all groups, the decreases were not statistically significant. These data suggest that certain HLA-DRB and DQB1 alleles, also associated with other T-cell-mediated skin diseases, may participate in the pathogenesis of or susceptibility to CTCL.

Chronic cutaneous lupus erythematosus mimicking mycosis fungoides.

Mycosis fungoides, which is characterized by a malignant infiltrate of T lymphocytes involving the epidermis, can be confused with other inflammatory skin diseases. We report the case of a patient with skin lesions containing an infiltrate of atypical lymphocytes with epidermotropism. This patient's condition was initially diagnosed as mycosis fungoides. Repeated biopsy samples had the histologic features of chronic cutaneous lupus erythematosus. The patient had a strongly positive antinuclear antibody response and the clinical lesions responded to hydroxychloroquine, however, and these findings led to an altered diagnosis. Other disorders that either clinically or histologically mimic mycosis fungoides are reviewed, and the diagnostic evaluation of patients in whom mycosis fungoides is suspected is summarized. Chronic cutaneous lupus erythematosus should be added to the list of diseases that can mimic mycosis fungoides.

Genetic polymorphism of the Gypsy population in Hungary as based on studies of red blood cell antigens.

Based on the examination of blood groups (ABO, Rh, MNSs, Duffy, Kell-Cellano, P, Kidd, Lewis, LW) the genetic polymorphism of the Gypsy population living in Hungary has been studied. Comparisons were made between Hungarian Gypsy and non-Gypsy populations, and significant differences were found in the incidence of most of the tested blood groups.