Journal of Alzheimer's Disease - Volume 23, issue 3

Authors: Briyal, Seema | Philip, Tina | Gulati, Anil

Article Type: Research Article

Abstract: Alzheimer's disease is a neurodegenerative disorder associated with abnormal accumulation of amyloid-β (Aβ) which can release endothelin (ET). The present study was conducted to investigate the effect of ET antagonists on Aβ-induced changes in ETA and ETB receptor expression, oxidative stress, and cognitive impairment. Male Sprague-Dawley rats were treated with Aβ1-40 in the lateral cerebral ventricles and were administered vehicle or ET antagonists for 14 days. Aβ treatment produced an increase in ETA receptor expression in the cerebral cortex, hippocampus, and brain stem by 72%, 85%, and 90%, respectively. No change in ETB receptor expression …was observed. There was an increase in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and superoxide dismutase (SOD) levels in Aβ-treated rats. In the Morris swim task, Aβ treated rats showed a significant impairment in spatial memory. ET receptor antagonists, BQ123, BMS182874, and TAK-044, significantly decreased Aβ-induced increase in ETA expression in the cortex, hippocampus, and brain stem. Rats treated with ET antagonists showed significant attenuation of Aβ-induced changes in the brain MDA, GSH, and SOD levels. Rats treated with specific ETA receptor antagonists, BQ123 and BMS182874, significantly reduced the cognitive impairment induced by Aβ. However, nonspecific ETA /ETB receptor antagonist TAK-044 did not show any improvement in the learning and memory parameter. This study demonstrates that ETA receptor antagonists are effective in preventing cognitive impairment, changes in ETA expression and oxidative stress induced by Aβ. It is concluded that ETA receptor antagonists may be useful in improving cognitive impairment due to Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, BQ123, cognitive deficit, endothelin, Morris water maze, oxidative stress, rats

DOI: 10.3233/JAD-2010-101245

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 491-503, 2011

Authors: Borroni, Barbara | Cerini, Carlo | Archetti, Silvana | Premi, Enrico | Cosseddu, Maura | Ferrari, Maria | Bellelli, Giuseppe | Gasparotti, Roberto | Caimi, Luigi | Di Luca, Monica | Padovani, Alessandro

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) refers to heterogeneous clinical and biological conditions. In FTLD, cerebrospinal fluid (CSF) tau levels have been reported highly variable. The aim of the present study was to evaluate whether CSF tau might be the hallmark of a distinct FTLD phenotype. Fifty-five FTLD patients, who underwent CSF analysis, were considered in the present study. In each patient, a wide standardized neuropsychological evaluation, and CSF tau, phospho-tau, and amyloid-β (Aβ) dosages were performed. Each patient was followed-up to five years, and outcomes carefully recorded. In a subgroup of patients (n = 24), magnetic resonance imaging scanning was performed, …by using voxel-based morphometry, for grey matter investigation. The higher the CSF tau levels, the worse the neuropsychological and neuroimaging pattern, mainly characterized by greater language disturbances and left temporal grey matter loss. The same pattern, even if less significant, was associated with CSF phospho-tau, while CSF Aβ levels did not play any influence on FTLD phenotype. FTLD patients with high CSF tau showed poor prognosis compared to those with low CSF tau (p = 0.031). In FTLD, CSF tau levels might be considered a marker of neurodegeneration, associated with a specific clinical and neuroimaging picture, and significantly related to poor outcome. Further studies aimed at defining the biological underpinnings of these findings are warranted. Show more

Keywords: Biological marker, cerebrospinal fluid, frontotemporal dementia, frontotemporal lobar degeneration, tau

DOI: 10.3233/JAD-2010-101407

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 505-512, 2011

Authors: Lerchundi, Rodrigo | Neira, Rodrigo | Valdivia, Sharin | Vio, Karin | Concha, Margarita I. | Zambrano, Angara | Otth, Carola

Article Type: Research Article

Abstract: Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic causes of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 infects limbic system structures in the central nervous system and has been suggested as an environmental risk factor for Alzheimer's disease. However, the possible mechanisms that link HSV-1 infection with the neurodegenerative process are still largely unknown. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation of tau epitopes serine202 /threonine205 and serine396 /serine404 …in neuronal cultures, resembling what occurs in neurodegenerative diseases. Therefore, the aim of the present study was to evaluate at the cellular level if another event associated with neurodegeneration, such as caspase-3 induced cleavage of tau, could also be triggered by HSV-1 infection in primary neuronal and astrocyte cultures. As expected, induction of caspase-3 activation and cleavage of tau protein at its specific site (aspartic acid 421) was observed by Western blot and immunofluorescence analyses in mice neuronal primary cultures infected with HSV-1. In agreement with our previous study on tau hyperphosphorylation, tau cleavage was also observed during the first 4 hours of infection, before neuronal death takes place. This tau processing has been previously demonstrated to increase the kinetics of tau aggregation in vitro and has also been observed in neurodegenerative pathologies. In conclusion, our findings support the idea that HSV-1 could contribute to induce neurodegenerative processes in age-associated pathologies such as Alzheimer's disease. Show more

Keywords: Alzheimer's disease, HSE, HSV-1, Neurodegeneration, TauC3

DOI: 10.3233/JAD-2010-101386

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 513-520, 2011

Authors: De Taboada, Luis | Yu, Jin | El-Amouri, Salim | Gattoni-Celli, Sebastiano | Richieri, Steve | McCarthy, Thomas | Streeter, Jackson | Kindy, Mark S.

Article Type: Research Article

Abstract: Transcranial laser therapy (TLT) was tested for efficacy in a mouse model of Alzheimer's disease (AD) using a near-infrared energy laser system. TLT is thought to stimulate ATP production, increase mitochondrial activity, and help maintain neuronal function. Studies were performed to determine the effect of TLT in an amyloid-β protein precursor (AβPP) transgenic mouse model. TLT was administered 3 times/week at various doses, starting at 3 months of age, and was compared to a control group (no laser treatment). Treatment was continued for a total of six months. Animals were examined for amyloid load, inflammatory markers, brain amyloid-β (Aβ) levels, …plasma Aβ levels, cerebrospinal fluid Aβ levels, soluble AβPP (sAβPP) levels, and behavioral changes. The numbers of Aβ plaques were significantly reduced in the brain with administration of TLT in a dose-dependent fashion. Administration of TLT was associated with a dose-dependent reduction in amyloid load. All TLT doses mitigated the behavioral effects seen with advanced amyloid deposition and reduce the expression of inflammatory markers in the AβPP transgenic mice. All TLT doses produced an increase in sAβPPα and a decrease in CTFβ levels consistent with inhibition of the β-secretase activity. In addition, TLT showed an increase in ATP levels, mitochondrial function, and c-fos suggesting an overall improvement in neurological function. These studies suggest that TLT is a potential candidate for treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid, animal models, laser therapy, transgenic mice

DOI: 10.3233/JAD-2010-100894

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 521-535, 2011

Authors: Ferrer, Isidro | Gómez, Ana | Carmona, Margarita | Huesa, Gema | Porta, Silvia | Riera-Codina, Miquel | Biagioli, Marta | Gustincich, Stefano | Aso, Ester

Article Type: Research Article

Abstract: Previous studies have demonstrated the presence of hemoglobin α-chain and β-chain in neurons of the rodent and human brain thus indicating that hemoglobin is a normal component of nerve cells and that hemoglobin may play a role in intraneuronal oxygen homeostasis. Progressing with these studies, hemoglobin expression has been examined in selected cell population in the brains of Alzheimer's disease (AD), argyrophilic grain disease (AGD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Double labeling immunofluorescence and confocal microscopy revealed reduced hemoglobin α-chain and β-chain in practically all neurons with small amounts of granular or punctuate hyperphosphorylated tau deposits …and in neurons with tangles in the hippocampus and frontal cortex in AD and in the hippocampus in AGD; in ballooned neurons containing αB-crystallin in the amygdala in AD and AGD; and in about 80% of neurons with punctuate α-synuclein deposits and in neurons with Lewy bodies in the substantia nigra pars compacta and in vulnerable neurons of the medulla oblongata in PD and DLB; and in neurons with Lewy bodies in the frontal cortex in DLB. Hemoglobin immunoreactivity was also observed in the core of neuritic plaques and in diffuse plaques, but not in dystrophic neurites. Loss of hemoglobin was specific as neuroglobin was present equally in neurons with and without abnormal protein inclusions, and erythropoietin receptor was expressed equally in neurons without and in neurons with abnormal protein aggregates in AD, AGD, PD, and DLB. Show more

Keywords: Alzheimer's disease, argyrophilic grain disease, dementia with Lewy bodies, erythropoietin receptor, hemoglobin, Parkinson disease

DOI: 10.3233/JAD-2010-101485

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 537-550, 2011

Authors: Zhang, Ying | He, Jin-Sheng | Wang, Xin | Wang, Jun | Bao, Fu-Xiang | Pang, Si-Yuan | Yin, Fan | Hu, Hong-Gang | Peng, Xiang-Lei | Sun, Wei-Min | Zheng, Yan-Peng | Hou, Ling-Ling | Hong, Tao

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) is recognized by many as the leading cause of Alzheimer's disease (AD), and Aβ oligomers play a major role in the early-onset form of AD. Recently, the application of passive immunization targeting Aβ has been investigated as a potential method of AD immunotherapy. We used a strain of monoclonal antibody against Aβ42 oligomers, designated A8, as an Aβ inhibitor to suppress Aβ aggregation and Aβ-derived cell toxicity in vitro, and as a passive immunotherapy approach to treat SAMP8 (senescence accelerated mouse sub-line P8) mice, an animal model of AD, in vivo. First, our results showed that …pre-incubation of A8 with Aβ oligomers inhibited both the maturation of Aβ fiber and Aβ oligomer toxicity on SH-SY5Y cells. Second, learning and memory was improved through intraperitoneal administration of A8 in SAMP8 mice. Third, Aβ pathology was ameliorated with decreased Aβ oligomers and phospho-tau levels in SAMP8 mice. Our data suggest that our monoclonal antibody A8 may be a candidate as a potential immunotherapeutic agent in AD. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, immunotherapy

DOI: 10.3233/JAD-2010-091195

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 551-561, 2011

Article Type: Other

DOI: 10.3233/JAD-2010-101426

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 563-565, 2011