Novel systemic delivery of a peptide-conjugated antisense oligonucleotide to reduce α-synuclein in a mouse model of Alzheimer's disease.

Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aß). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease, and Dementia with Lewy Bodies, but less so in Alzheimer's Disease (AD), despite the fact that accumulation of α-syn has been confirmed in over 50% of postmortem brains neuropathologically diagnosed with AD. To date, no therapeutic strategy has effectively or consistently downregulated α-syn in AD. Here we tested the hypothesis that by using a systemically-delivered peptide (ApoB11) bound to a modified antisense oligonucleotide against α-syn (ASO-α-syn), we can downregulate α-syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. Our results demonstrate that monthly systemic treatment with of ApoB11:ASO α-syn beginning at 6 months of age reduces expression of α-synuclein in the brains of 9-month-old AD mice. Downregulation of α-syn led to reduction in Aß plaque burden, prevented neuronal loss and astrogliosis. Furthermore, we found that AD mice treated with ApoB11:ASO α-syn had greatly improved hippocampal and spatial memory function in comparison to their control counterparts. Collectively, our data supports the reduction of α-syn through use of systemically-delivered ApoB11:ASO α-syn as a promising future disease-modifying therapeutic for AD.

Association of mannose-binding lectin 2 gene polymorphisms with Guillain-Barré syndrome.

Complement activation plays a critical role in the pathogenesis of Guillain-Barré syndrome (GBS), a debilitating immune-mediated neuropathy. Mannose-binding lectin (MBL) is a complement activation factor of lectin pathway which as genetic host factor may influence the susceptibility or severity of GBS. We investigated the frequency of MBL2 promoter (- 550H/L and - 221X/Y) and functional region (exon 1 A/O) polymorphisms and their association with disease susceptibility, clinical features and serum MBL among GBS patients (n = 300) and healthy controls (n = 300) in Bangladesh. The median patient age was 30 years (IQR: 18-42; males, 68%). MBL2 polymorphisms were not significantly associated with GBS susceptibility compared to healthy controls. HL heterozygosity in GBS patients was significantly associated with mild functional disability at enrolment (P = 0.0145, OR, 95% CI 2.1, 1.17-3.82). The HY, YA, HA and HYA heterozygous haplotypes were more common among mildly affected (P = 0.0067, P = 0.0086, P = 0.0075, P = 0.0032, respectively) than severely affected patients with GBS. Reduced serum MBL was significantly associated with the LL, OO and no HYA variants and GBS disease severity. No significant association was observed between MBL2 polymorphisms and electrophysiological variants, recent Campylobacter jejuni infection or anti-ganglioside (GM1) antibody responses in GBS. In conclusion, MBL2 gene polymorphisms are related to reduced serum MBL and associated with the severity of GBS.

Toll-like receptor-4 299Gly allele is associated with Guillain-Barré syndrome in Bangladesh.

OBJECTIVE: TLR4 plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS). The relationships between TLR4 polymorphisms and susceptibility to GBS are poorly understood. We investigated the frequency and assessed the association of two single nucleotide polymorphisms (SNPs) in the extracellular domain of TLR4 (Asp299Gly and Thr399Ile) with disease susceptibility and the clinical features of GBS in a Bangladeshi cohort. METHODS: A total of 290 subjects were included in this study: 141 patients with GBS and 149 unrelated healthy controls. The TLR4 polymorphisms Asp299Gly and Thr399Ile were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: The minor 299Gly allele was significantly associated with GBS susceptibility (P = 0.0137, OR = 1.97, 95% CI = 1.17-3.31), and was present at a significantly higher frequency in patients with the acute motor axonal neuropathy (AMAN) subtype of GBS (P = 0.0120, OR = 2.37, 95% CI = 1.26-4.47) than acute inflammatory demyelinating polyneuropathy (AIDP) subtype (P = 0.961, OR = 1.15, 95% CI = 0.38-3.48); when compared to healthy controls. The genotype frequency of the Asp299Gly polymorphism was not significantly different between patients with GBS and healthy controls. The Asp299-Thr399 haplotype was associated with a significantly lower risk of developing GBS (P = 0.0451, OR = 0.63, 95% CI = 0.40-0.99). No association was observed between the Thr399Ile polymorphism and GBS disease susceptibility. INTERPRETATION: The TLR4 minor 299Gly allele was associated with increased susceptibility to GBS and the axonal GBS subtype in the Bangladeshi population. However, no associations were observed between the genotypes of the Asp299Gly and Thr399Ile SNPs and antecedent C. jejuni infection or disease severity in Bangladeshi patients with GBS.

CD1A and CD1E gene polymorphisms are not associated with susceptibility to Guillain-Barré syndrome in the Bangladeshi population.

The post-infectious autoimmune polyradiculoneuropathy Guillain-Barré syndrome (GBS) is triggered by molecular mimicry between microbial glycolipid antigens and human peripheral nerve gangliosides. Single nucleotide polymorphisms in exon 2 of CD1A (*01/*02) and CD1E (*01/*02) were assessed using PCR-RFLP; no significant differences in genotype or allele frequency were observed between 200 patients with GBS and 200 healthy controls. CD1 gene polymorphisms cannot be recognized as a susceptibility or disease-causative factor for GBS in the Bangladeshi population. However, further studies are necessary to investigate the CD1A*01/CD1E*01 haplotype distribution and its potential causative role in the axonal form of GBS.

FAS promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5-4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3-5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4-2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3-10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS.

Tumor necrosis factor-alpha -863C/A polymorphism is associated with Guillain-Barré syndrome in Bangladesh.

Guillain-Barré syndrome (GBS) is a post-infectious autoimmune polyneuropathy regulated by pro- and anti-inflammatory cytokines; TNFA polymorphisms may exert immune pathogenic roles in GBS. We assessed TNFA promoter region polymorphisms (-238G/A, -308G/A, -857C/T, -863C/A) in Bangladeshi patients with GBS (n=300) and healthy controls (n=300) by PCR-RFLP and ASO-PCR. TNFA -863CA was significantly associated with GBS disease susceptibility (P=0.0154) and disease severity (P=0.0492). TNFA -238A allele was more frequent among anti-ganglioside (GM1) antibody-positive patients (P=0.0092) and -863AA associated with AMAN subtype of GBS (P=0.0398). TNFA -863C/A may contribute to GBS severity and pathogenesis in Bangladeshi patients.