Journal of Alzheimer's Disease - Volume 33, issue 1

Authors: del Ser, Teodoro | Steinwachs, Klaus C. | Gertz, Hermann J. | Andrés, María V. | Gómez-Carrillo, Belén | Medina, Miguel | Vericat, Joan A. | Redondo, Pilar | Fleet, David | León, Teresa

Article Type: Research Article

Abstract: This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical …Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD. Show more

Keywords: Alzheimer's disease, clinical trial, glycogen synthase kinase-3, pharmacological treatment, tideglusib

DOI: 10.3233/JAD-2012-120805

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 205-215, 2013

Authors: Wang, Ju | Shi, Zi-Qi | Xu, Xiaojun | Xin, Gui-Zhong | Chen, Jun | Qi, Lian-Wen | Li, Ping

Article Type: Research Article

Abstract: Triptolide, a biologically active natural product from Tripterygium wilfordii, protects neurons from inflammation-mediated damage. Our results showed for the first time that triptolide inhibited the expression of CXCR2 and presenilin in a neuroblastoma cell line SHSY5Ysw. Moreover, triptolide potently inhibited amyloid-β1-42 production with IC50 value of 30 pM in HEK293sw cells or 2 nM in SHSY5Ysw cells, respectively. We also demonstrated that triptolide prevented primary cortical neurons from chemokine CXCL1-induced cytotoxicity. Therefore, our study indicates that the neural protective effect of triptolide is largely mediated by inhibiting CXCR2 activity.

Keywords: Alzheimer's disease, amyloid-β, CXCR2, γ-secretase, neuroprotective, triptolide

DOI: 10.3233/JAD-2012-120841

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 217-229, 2013

Authors: Lonskaya, Irina | Shekoyan, Ashot R. | Hebron, Michaeline L. | Desforges, Nicole | Algarzae, Norah K. | Moussa, Charbel E.-H.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is an aging disorder characterized by amyloid-β (Aβ) accumulation in extracellular plaques and formation of intracellular tangles containing hyperphosphorylated tau (p-Tau). Autophagic defects, leading to accumulation of autophagosomes, are recognized in AD. Parkin is an E3 ubiquitin ligase involved in degradation of proteins via autophagy and the proteasome. We investigated the role of parkin in postmortem brain tissues from 21 AD patients and 15 control subjects. We detected decreased parkin solubility in AD cortex and parkin co-localization with intraneuronal Aβ1-42 in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aβ and p-Tau was …detected in autophagosomes in AD brains. To determine the role of parkin in Aβ clearance, we generated gene transfer animals expressing lentiviral Aβ1-42 with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aβ1-42 led to p-Tau accumulation and induced autophagic defects, leading to accumulation of autophagic vacuoles. However, co-expression of wild type parkin facilitated autophagic clearance and promoted deposition of Aβ1-42 and p-Tau into the lysosome. Taken together, these data suggest that Aβ1-42 alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aβ1-42 and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation. Show more

Keywords: amyloid-β, autophagy, parkin, tau phosphorylation

DOI: 10.3233/JAD-2012-121141

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 231-247, 2013

Authors: Sahara, Naruhiko | DeTure, Michael | Ren, Yan | Ebrahim, Abdul-Shukkur | Kang, Dongcheul | Knight, Joshua | Volbracht, Christiane | Pedersen, Jan Torleif | Dickson, Dennis W. | Yen, Shu-Hui | Lewis, Jada

Article Type: Research Article

Abstract: Conditional overexpression of four-repeat human tau containing the P301L missense mutation in the rTg4510 mouse model of tauopathy leads to progressive accumulation of neurofibrillary tangles and hyperphosphorylated, sarkosyl-insoluble tau species, which are biochemically comparable to abnormal tau characteristic of hereditary tauopathies termed FTDP-17. To fully understand the impact of tau species at different stages of self-assembly on neurodegeneration, we fractionated rTg4510 brain representing several stages of tauopathy to obtain TBS-extractable (S1), high salt/sarkosyl-extractable (S3), and sarkosyl-insoluble (P3) fractions. Under reducing condition, the S1 fraction was demonstrated by western blotting to contain both 50–60 kDa normally-sized and 64 kDa tau. Both …are thermo-stable, but the 64 kDa tau showed a higher degree of phosphorylation. Under non-reducing condition, nearly all TBS-extractable 64 kDa tau were detected as ∼130 kDa species consistent with the size of dimer. Quantitative analysis showed ∼80 times more 64 kDa tau in S1 than P3 fraction. Immunoelectron microscopy revealed tau-positive granules/short filaments in S1 fraction. These structures displayed MC1 immunoreactivities indicative of conformational/pathological change of tau. MC1 immunoreactivity was detected by dot blotting in samples from 2.5 month-old mice, whereas Ab39 immunoreactivity indicative of late stages of tau assembly was detected only in P3 fraction. Quantitative analysis also demonstrated a significant inverse correlation between brain weight and 64 kDa tau, but the level of TBS-extractable 64 kDa tau reflects neurodegeneration better than that of sarkosyl-insoluble 64 kDa tau. Together, the findings suggest that TBS-extractable 64 kDa tau production is a potential target for therapeutic intervention of tauopathies. Show more

Keywords: Dimer, FTDP-17, hyperphosphorylation, tau protein, tauopathy, transgenic mice

DOI: 10.3233/JAD-2012-121093

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 249-263, 2013

Authors: La Rosa, Luca Rosario | Matrone, Carmela | Ferraina, Caterina | Panico, Maria Beatrice | Piccirilli, Silvia | Di Certo, Maria Grazia | Strimpakos, Georgios | Mercuri, Nicola Biagio | Calissano, Pietro | D'Amelio, Marcello | Nisticò, Robert

Article Type: Research Article

Abstract: Amyloid-β protein precursor (AβPP) is a ubiquitous protein found in all cell types, suggesting basic and yet important roles, which still remain to be fully elucidated. Loss of function of AβPP has been linked to abnormal neuronal morphology and synaptic function within the hippocampus and alterations in spatial learning, suggesting a neurotrophic role for this protein. Besides AβPP, nerve growth factor (NGF) and other neurotrophins have also been shown to finely modulate neuronal excitability, synaptic plasticity, and cognitive functions. In addition, recent data support the hypothesis of a functional interconnection between AβPP and NGF pathway. Here, we demonstrated that loss …of AβPP function, leading to progressive decrease of choline acetyltransferase expression in the septum, correlates with age-related impairment of long-term potentiation (LTP) in the dentate gyrus. We next addressed whether impaired hippocampal plasticity in AβPP-null mice can be restored upon NGF treatment. Notably, NGF, as well as Pro-NGF, can fully revert LTP deficits in AβPP-null mice through p75NTR and JNK pathway activation. Overall the present study may unveil a new mechanism by which, in the absence of AβPP, NGF treatment may preferentially direct p75-neurotrophin-dependent JNK activation toward regeneration and plasticity in functionally relevant brain circuits. Show more

Keywords: Amyloid-β protein precursor, c-jun N-terminal kinase, dentate gyrus, long-term potentiation, nerve growth factor, p75NTR

DOI: 10.3233/JAD-2012-112108

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 265-272, 2013

Authors: Varjassyová, Alexandra | Hořínek, Daniel | Andel, Ross | Amlerova, Jana | Laczó, Jan | Sheardová, Kateřina | Magerová, Hana | Holmerová, Iva | Vyhnálek, Martin | Bradáč, Ondřej | Geda, Yonas E. | Hort, Jakub

Article Type: Research Article

Abstract: We examined whether recognition of facial emotional expression would be affected in amnestic mild cognitive impairment (aMCI). A total of 50 elderly persons met the initial inclusion criteria; 10 were subsequently excluded (Geriatric Depression Score > 5). 22 subjects were classified with aMCI based on published criteria (single domain aMCI [SD-aMCI], n = 10; multiple domain aMCI [MD-aMCI], n = 12); 18 subjects were cognitively normal. All underwent standard neurological and neuropsychological evaluations as well as tests of facial emotion recognition (FER) and famous faces identification (FFI). Among normal controls, FFI was negatively correlated with Mini-Mental Status Examination scores and …positively correlated with executive function. Among patients with aMCI, FER was correlated with attention/speed of processing. No other correlations were significant. In a multinomial logistic regression model adjusted for age, gender, and education, a poorer score on FER, but not on FFI, was associated with greater odds of being classified as MD-aMCI (odds ratio [OR], 3.82; 95% confidence interval [CI], 1.05–13.91; p = 0.042). This association was not explained by memory or global cognitive score. There was no association between FER or FFI and SD-aMCI (OR, 1.13; 95% CI, 0.36–3.57; p = 0.836). Therefore, FER, but not FFI, may be impaired in MD-aMCI. This implies that in MD-aMCI, the tasks of FER and FFI may involve segregated neurocognitive networks. Show more

Keywords: Assessment of cognitive disorders/dementia, cognitive aging, emotion, mild cognitive impairment, neuropsychiatric symptoms

DOI: 10.3233/JAD-2012-120148

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 273-280, 2013

Article Type: Other

DOI: 10.3233/JAD-2012-120914

Citation: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 281-282, 2013