Journal of Alzheimer's Disease - Volume 41, issue 4

Authors: Yang, Meifeng | Lu, Jing | Miao, Junye | Rizak, Joshua | Yang, Jianzhen | Zhai, Rongwei | Zhou, Jun | Qu, Jiagui | Wang, Jianhong | Yang, Shangchuan | Ma, Yuanye | Hu, Xintian | He, Rongqiao

Article Type: Research Article

Abstract: Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found …to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology. Show more

Keywords: Alzheimer's disease, cognitive impairment, disease progression, formaldehyde, methanol, tau hyperphosphorylation

DOI: 10.3233/JAD-131529

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1117-1129, 2014

Authors: Yang, Meifeng | Miao, Junye | Rizak, Joshua | Zhai, Rongwei | Wang, Zhengbo | Huma, Tanzeel | Li, Ting | Zheng, Na | Wu, Shihao | Zheng, Yingwei | Fan, Xiaona | Yang, Jianzhen | Wang, Jianhong | Yang, Shangchuan | Ma, Yuanye | Lü, Longbao | He, Rongqiao | Hu, Xintian

Article Type: Research Article

Abstract: A recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology has provided a new impetus to investigate the chronic effects of methanol exposure. This paper expands this investigation to the non-human primate, rhesus macaque, through the chronic feeding of young male monkeys with 3% methanol ad libitum. Variable Spatial Delay Response Tasks of the monkeys found that the methanol feeding led to persistent memory decline in the monkeys that lasted 6 months beyond the feeding regimen. This change coincided with increases in tau protein phosphorylation at residues T181 and S396 in cerebrospinal fluid during feeding as …well as with increases in tau phosphorylated aggregates and amyloid plaques in four brain regions postmortem: the frontal lobe, parietal lobe, temporal lobe, and the hippocampus. Tau phosphorylation in cerebrospinal fluid was found to be dependent on methanol feeding status, but phosphorylation changes in the brain were found to be persistent 6 months after the methanol feeding stopped. This suggested the methanol feeding caused long-lasting and persistent pathological changes that were related to AD development in the monkey. Most notably, the presence of amyloid plaque formations in the monkeys highlighted a marked difference in animal systems used in AD investigations, suggesting that the innate defenses in mice against methanol toxicity may have limited previous investigations into AD pathology. Nonetheless, these findings support a growing body of evidence that links methanol and its metabolite formaldehyde to AD pathology. Show more

Keywords: Alzheimer's disease, amyloid plaque formation, cognitive impairment, disease progression, formaldehyde, methanol toxicity, tau hyperphosphorylation

DOI: 10.3233/JAD-131532

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1131-1147, 2014

Authors: Lin, Li | Yang, Shu-Sheng | Chu, Jiang | Wang, Lu | Ning, Lin-Na | Zhang, Teng | Jiang, Qian | Tian, Qing | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Region-specific neurodegeneration was reported in brains of Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we studied the expression of some AD-associated proteins in temporal cortex, frontal cortex, cerebellum, and hippocampus of 4-month-old male Sprague-Dawley rats. Levels of the phosphorylated tau at Thr231, Ser396, and Ser202/Thr205, phosphorylated amyloid-β protein precursor (AβPP) and amyloid-β, synapse-associated proteins glutamate receptors 2, N-methyl-D-aspartic receptors 1 (NR1), NR2A, NR2B, and postsynaptic density protein 95 were much lower in cerebellum, while the levels of total tau, phosphorylated tau at Thr205, Ser214, Ser262, and Ser198/199/202 epitopes, and total AβPP were similar in the four …brain regions. As endoplasmic reticulum (ER) stress was reported in the early stage of AD, we injected tunicamycin, an ER stress inducer, into the lateral ventricular of rats and 48 hours later found in the other three brain regions but not cerebellum, increasing of binding immunoglobulin protein with the increased phosphorylation of pancreatic ER kinase, inositol-requiring enzyme 1, and activating transcription factor 6. Simultaneously, levels of phosphorylated tau at all of the above sites were significantly increased with the activation of glycogen synthase kinase-3β in temporal cortex, frontal cortex, and/or hippocampus, but not cerebellum. The synapse-associated proteins, GluR2, PSD95, and synapsin1, were found decreased in the hippocampus after tunicamycin exposure. These data together may partially explain why the AD-like neuropathology, such as formation of neurofibrillary tangles, was rarely detected in cerebellum. Show more

Keywords: Cerebellum, endoplasmic reticulum stress, frontal cortex, hippocampus, synaptic protein, tau, temporal cortex

DOI: 10.3233/JAD-140207

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1149-1163, 2014

Authors: Qiao, Feng | Gao, Xiu-Ping | Yuan, Li | Cai, Hong-Yan | Qi, Jin-Shun

Article Type: Research Article

Abstract: Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the …CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+ /calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4. Show more

Keywords: Apolipoprotein E4, Ca2+/calmodulin-dependent protein kinase II (CaMKII), cAMP response element-binding protein (CREB), hippocampus, late-phase long-term potentiation, synaptic plasticity

DOI: 10.3233/JAD-140375

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1165-1176, 2014

Authors: Fu, YuHong | Rusznák, Zoltán | Kwok, John B.J. | Kim, Woojin Scott | Paxinos, George

Article Type: Research Article

Abstract: The J20 mouse expresses human mutant amyloid-β protein precursor (hAβPPSwInd) and is an established transgenic model of Alzheimer's disease (AD). From the age of 5 months, amyloid-β (Aβ) deposits appear in the hippocampus with concomitant increase of AD-associated features. Although changes occurring after the appearance of Aβ deposits have been extensively studied, very little is known about alterations that occur prior to 5 months. The present study aimed to identify changes in the cellular composition and proliferative potential of the J20 hippocampus using 1–18-month-old mice. Neuronal, non-neuronal, Ki-67+, and TUNEL+ cell numbers were counted with the isotropic fractionator method. Age-dependent …changes of the expression of microglia-, astrocyte-, and neurogenesis-specific markers were sought in the entire hippocampus. Several transgene-associated changes were revealed before the appearance of Aβ deposits. The number of proliferating cells decreased whereas the number of microglia clusters increased as early as 4 weeks of age. The neurogenesis was also impaired in the dentate gyrus of 7–11-week-old J20 mice. A statistically significant negative correlation was found between the number of proliferating cells and age in both populations, but the time course of the age-dependence was steeper in wild-type than in J20 mice. Negative age-dependence was noted when the number of cells committed to apoptosis was examined. Our results indicate that overexpression of mutant hAβPP initiates a cascade of pathologic events well before the appearance of visible Aβ plaques. Accordingly, early signs of AD include reduced cell proliferation, impaired neurogenesis, and increased activity of microglia in the hippocampus. Show more

Keywords: Alzheimer's disease, cellular constituents, hippocampus, J20, neurogenesis, microglia, proliferation

DOI: 10.3233/JAD-132717

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1177-1192, 2014

Authors: Zhang, Ling | Liu, Cui | Wu, Jie | Tao, Jing-jing | Sui, Xiao-long | Yao, Zhi-gang | Xu, Yan-feng | Huang, Lan | Zhu, Hua | Sheng, Shu-li | Qin, Chuan

Article Type: Research Article

Abstract: Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 …not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid, autophagy, histone deacetylase (HDAC), tau

DOI: 10.3233/JAD-140066

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1193-1205, 2014

Authors: Waragai, Masaaki | Hata, Saori | Suzuki, Toshiharu | Ishii, Ryotaro | Fujii, Chihiro | Tokuda, Takahiko | Arai, Hiroyuki | Ohrui, Takashi | Higuchi, Susumu | Yoshida, Madoka | Igarashi, Kazuei | Moriya, Masaru | Iwai, Naomichi | Uemura, Kenichi

Article Type: Research Article

Abstract: We validated the utility of SPM8 plus DARTEL (VSRAD) combined with magnetic resonance spectroscopy (1 H MRS) as an adjunct screening technique for dementia due to Alzheimer's disease (AD). We examined the posterior cingulate gyri of 228 subjects using VSRAD and 1 H MRS in addition to conventional cerebrospinal fluid biomarkers at baseline. At the 3-year follow-up, the 228 subject were classified as follows: 93 healthy subjects, 42 MCI-non-converters (MCI-NC), 25 MCI-converters to AD (MCI-C), 44 AD, 8 dementia with Lewy bodies (DLB), 5 normal pressure hydrocephalus, and 11 patients with other neurological diseases. Our results demonstrated that subjects with …increased medial temporal atrophy (MTA) severity on VSRAD, increased Cho/Cr, MI/Cr ratio, and decreased NAA/Cr and NAA/MI ratio on 1 H MRS at baseline were at risk of dementia due to AD. Receiver operating characteristic analysis showed that severity of MTA and the NAA/MI ratio distinguished patients with AD and MCI-C from controls. Furthermore, the 118 subjects without dementia and MTA showing only a decreased NAA/MI ratio at baseline developed to MCI-C, AD, and DLB 3 years later. 1 H MRS detected biochemical abnormalities preceding brain atrophy and cognitive decline. VSRAD combined with 1 H MRS may be routinely applied to screen for MCI/AD and prodromal AD in clinical practice. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, magnetic resonance spectroscopy (1H MRS), screening, SPM8 plus DARTEL (VSRAD), surrogate marker

DOI: 10.3233/JAD-132786

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1207-1222, 2014

Authors: Taipale, Heidi | Koponen, Marjaana | Tanskanen, Antti | Tolppanen, Anna-Maija | Tiihonen, Jari | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Antipsychotic polypharmacy (APP) is not recommended in treatment of behavioral and psychological symptoms of dementia (BPSD). There is lack of studies concerning prevalence of APP among persons with dementia. Objectives: The objective of our study was to describe prevalence and risk factors associated with antipsychotic polypharmacy among antipsychotic users with Alzheimer’s disease (AD). Methods: Data from nationwide MEDALZ-2005 cohort including all community-dwelling persons diagnosed with AD in Finland was utilized. Register-based data included prescriptions, comorbidities, and hospital discharge diagnoses. Users of antipsychotics during 2006–2009 were included (n = 9,803). The risk of starting antipsychotic polypharmacy …was evaluated with Cox proportional hazards model. Results: Prevalence of antipsychotic polypharmacy was 8% (n = 750) among antipsychotic users (n = 9,803). Quetiapine and risperidone was the most common combination of two antipsychotics followed by combination of quetiapine and haloperidol. Antipsychotic polypharmacy was associated with younger age (HR 1.35 [Confidence Interval, CI, 1.16–1.56]), male gender (HR 1.18 [CI 1.02–1.38]), and history of psychiatric disorder (HR 1.50 [CI 1.26–1.78]) in the adjusted model. Conclusions: In conclusion, we found higher prevalence of APP than previously reported among older populations. This is concerning since effectiveness of APP has not been demonstrated and APP is not recommended in the treatment of BPSD. Clinicians should pay more attention to avoid APP and use of antipsychotics to other indications than BPSD among persons with AD. Show more

Keywords: Alzheimer's disease, antipsychotics, antipsychotic polypharmacy, prescription register

DOI: 10.3233/JAD-140282

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1223-1228, 2014

Authors: Krajcovicova, Lenka | Mikl, Michal | Marecek, Radek | Rektorova, Irena

Article Type: Research Article

Abstract: Changes in connectivity of the posterior node of the default mode network (DMN) were studied when switching from baseline to a cognitive task using functional magnetic resonance imaging. In all, 15 patients with mild to moderate Alzheimer's disease (AD) and 18 age-, gender-, and education-matched healthy controls (HC) participated in the study. Psychophysiological interactions analysis was used to assess the specific alterations in the DMN connectivity (deactivation-based) due to psychological effects from the complex visual scene encoding task. In HC, we observed task-induced connectivity decreases between the posterior cingulate and middle temporal and occipital visual cortices. These findings imply successful …involvement of the ventral visual pathway during the visual processing in our HC cohort. In AD, involvement of the areas engaged in the ventral visual pathway was observed only in a small volume of the right middle temporal gyrus. Additional connectivity changes (decreases) in AD were present between the posterior cingulate and superior temporal gyrus when switching from baseline to task condition. These changes are probably related to both disturbed visual processing and the DMN connectivity in AD and reflect deficits and compensatory mechanisms within the large scale brain networks in this patient population. Studying the DMN connectivity using psychophysiological interactions analysis may provide a sensitive tool for exploring early changes in AD and their dynamics during the disease progression. Show more

Keywords: Alzheimer's disease, default mode network, functional MRI, posterior cingulate, visual processing

DOI: 10.3233/JAD-131208

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1229-1238, 2014

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Bramanti, Placido | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Modern analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity. To test the hypothesis that aging processes modulate the brain connectivity network, EEG recording was conducted on 113 healthy volunteers. They were divided into three groups in accordance with their ages: 36 Young (15–45 years), 46 Adult (50–70 years), and 31 Elderly (>70 years). To evaluate the stability of the investigated parameters, a subgroup of 10 subjects underwent a second EEG recording two weeks later. Graph theory functions were applied to the undirected and weighted networks obtained by the lagged linear coherence evaluated by eLORETA on cortical sources. …EEG frequency bands of interest were: delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). The spectral connectivity analysis of cortical sources showed that the normalized Characteristic Path Length (λ) presented the pattern Young > Adult>Elderly in the higher alpha band. Elderly also showed a greater increase in delta and theta bands than Young. The correlation between age and λ showed that higher ages corresponded to higher λ in delta and theta and lower in the alpha2 band; this pattern reflects the age-related modulation of higher (alpha) and decreased (delta) connectivity. The Normalized Clustering coefficient (γ) and small-world network modeling (σ) showed non-significant age-modulation. Evidence from the present study suggests that graph theory can aid in the analysis of connectivity patterns estimated from EEG and can facilitate the study of the physiological and pathological brain aging features of functional connectivity networks. Show more

Keywords: Delta and alpha bands, EEG, eLORETA, functional connectivity, graph theory, small-world networks

DOI: 10.3233/JAD-140090

Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1239-1249, 2014