Journal of Alzheimer's Disease - Volume 23, issue 4

Authors: Tomljenovic, Lucija

Article Type: Review Article

Abstract: The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently …excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have mislead scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD. Show more

Keywords: Aging, aluminum, Alzheimer's disease, amyloidosis, bioavailability, brain compartmentalization, cholinergic dysfunction, G-proteins, neurofibrillary tangles, neurotoxicity

DOI: 10.3233/JAD-2010-101494

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 567-598, 2011

Authors: Banks, William A. | Kumar, Vijaya B. | Farr, Susan A. | Nakaoke, Ryota | Robinson, Sandra M. | Morley, John E.

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) influences brain levels of amyloid-β (Aβ) by transporting Aβ out of the brain (efflux) and by the reabsorption of cerebrospinal fluid (CSF) into the blood stream (bulk flow). In Alzheimer's disease (AD) and normal aging, unknown factors impair Aβ efflux and bulk flow in aging and in AD. These impairments have been proposed as mechanisms by which the Aβ burden in brain can increase. Impairment in Aβ efflux occurs in animal models of AD, including the aged SAMP8 mouse. Here, we show that CSF reabsorption is also reduced by about 50% in SAMP8 mice (p < …0.05). We then determined whether an antisense directed at the Aβ region of the amyloid-β protein precursor (AβPP) and previously shown to decrease brain levels of AβPP and to reverse the cognitive impairments of the SAMP8 mouse was able to reverse these impairments. We found that the antisense restored both the CSF reabsorption, more than doubling the rate of efflux, and the saturable efflux of Aβ. These findings suggest that AβPP/Aβ itself contributes to the impairments in bulk flow and saturable efflux of Aβ and that reduction of AβPP/Aβ levels can restore normal function of the BBB. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, antisense, blood-brain barrier, bulk flow, SAMP8

DOI: 10.3233/JAD-2010-100021

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 599-605, 2011

Authors: Gelber, Rebecca P. | Petrovitch, Helen | Masaki, Kamal H. | Ross, G. Webster | White, Lon R.

Article Type: Research Article

Abstract: While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965–1968) examined for dementia in 1991–1993, including 418 decedents (1992–2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia …(VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (>277.5 mg/d) were less likely than men in the lowest quartile (≤115.5 mg) to have any of the lesion types (adjusted-OR, 0.45; 95% CI, 0.23–0.89; p, trend = 0.04). Coffee and caffeine intake in midlife were not associated with cognitive impairment, dementia, or individual neuropathologic lesions, although higher caffeine intake was associated with a lower odds of having any of the lesion types at autopsy. Show more

Keywords: Caffeine, coffee, cohort studies, dementia

DOI: 10.3233/JAD-2010-101428

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 607-615, 2011

Authors: Qian, Wei | Yin, Xiaomin | Hu, Wen | Shi, Jianhua | Gu, Jianlan | Grundke-Iqbal, Inge | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Protein phosphatase 2B (PP2B) is one of the major brain phosphatases and can dephosphorylate tau at several phosphorylation sites in vitro. Previous studies that measured PP2B activity in human brain crude extracts showed that PP2B activity was either unchanged or decreased in Alzheimer's disease (AD) brain. These results led to the speculation that PP2B might regulate tau phosphorylation and that a down-regulation of PP2B might contribute to abnormal hyperphosphorylation of tau. In this study, we immunoprecipitated PP2B from brains of six AD subjects and seven postmortem- and age-matched controls and then measured the phosphatase activity. We found a three-fold increase …in PP2B activity in AD brain as compared with control brains. The activation was due to the partial cleavage of PP2B by calpain I that was activated in AD brain. The truncation of PP2B appeared to alter its intracellular distribution in the brain. In human brains, PP2B activity correlated positively, rather than negatively, to the levels of tau phosphorylation at several sites that can be dephosphorylated by PP2B in vitro. Truncation of PP2B in the frontal cortex was more than in the temporal cortex, and tau phosphorylation was also more in the frontal cortex. Taken together, these results indicate that truncation of PP2B by calpain I elevates its activity but does not counteract the abnormal hyperphosphorylation tau in AD brain. Show more

Keywords: Alzheimer's disease, calpain, hyperphosphorylation, protein phosphatase 2B, tau

DOI: 10.3233/JAD-2010-100987

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 617-627, 2011

Authors: Manaye, Kebreten F. | Allard, Joanne S. | Kalifa, Sara | Drew, Amy C. | Xu, Guang | Ingram, Donald K. | de Cabo, Rafael | Mouton, Peter R.

Article Type: Research Article

Abstract: Quantitative microanalysis of brains from patients with Alzheimer's disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD-associated mutations, amyloid-β protein precursor (AβPPswe ) and presenilin 1 (PS1ΔE9 ), undergo significant AD-type neuron loss in sub-cortical nuclei with heavy catecholaminergic projections to the hippocampal formation. Here we report that by 13 months of age these dtg AβPPswe /PS1ΔE9 mice also show significant loss of pyramidal neuron in a critical region for …learning and memory, the CA1 subregion of hippocampus, as a direct function of amyloid-β (Aβ) aggregation. We used these mice to test whether 17α-estradiol (17αE2), a less feminizing and non-carcinogenic enantiomer of 17β-estradiol, protects against this CA1 neuron loss. Female dtg AβPPswe /PS1ΔE9 mice were ovariectomized at 8–9 months of age and treated for 60 days with either 17αE2 or placebo via subcutaneous pellets. Computerized stereology revealed that 17αE2 ameliorated the loss of neurons in CA1 and reduced microglial activation in the hippocampus. These findings support the view that 17αE2, which may act through non-genomic mechanisms independent of traditional estrogen receptors, could prevent or delay the progression of AD in older men and women. Show more

Keywords: Alzheimer’s disease, amyloid-β, stereology, transgenic mice

DOI: 10.3233/JAD-2010-100993

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 629-639, 2011

Authors: Zhu, Lei | Yu, Jianchun | Shi, Qiaoqiao | Lu, Wenwen | Liu, Bin | Xu, Shaofeng | Wang, Ling | Han, Jingxian | Wang, Xiaoliang

Article Type: Research Article

Abstract: In order to discover and identify the key protein biomarkers in the aging process, we performed a differential proteomic analysis of hippocampus and cortex in 5- and 15-month old senescence-accelerated mouse prone 8 (SAMP8) as well as in control strain SAM/resistant 1 (SAMR1). Using 2-DE combined with MALDI TOF/TOF mass spectrometry, about 1700 protein spots were isolated, and three groups of differentially expressed proteins were identified. The first group contained the strain-specific and non-age-related differential proteins that were differentially expressed in SAMP8 compared with SAMR1 mice. The changes might be implicated in the genetic difference between SAMP8 and SAMR1 mice; …specifically, the proteins ubiquitin carboxyl-terminal esterase L3, mitofilin, adenylate kinase 4, and an unnamed protein product (gi|12847201). The proteins in the second group were age-specific, which were differentially expressed between 5- and 15-month old SAM mice. Those proteins are particularly interesting since the changes were aging-related and some of them were previously reported to be expressed in Alzheimer's disease patients. These proteins included N-myc downstream regulated gene 2, enolase 2, Cu/Zn superoxide dismutase, myosin, and two unnamed protein products (gi|74214304 and gi|74178239). The protein in the third group was SAMP8 specific-age-related protein, which was identified as heme binding protein 1. The present study provides new information about SAMP8 specific and aging-related protein changes in brain. Further investigations will be performed to reveal the significance of these proteins in brain aging process and the potential roles as biomarkers for effective diagnosis and therapy. Show more

Keywords: Brain aging, cortex, hippocampus, proteomics, senescence-accelerated mouse

DOI: 10.3233/JAD-2010-101389

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 641-654, 2011

Authors: Mak, Henry Ka-Fung | Zhang, Zhipeng | Yau, Kelvin Kai-Wing | Zhang, Linda | Chan, Queenie | Chu, Leung-Wing

Article Type: Research Article

Abstract: Quantitative MRI of the hippocampus has been increasingly employed as a biomarker in Alzheimer's disease (AD). We compare voxel-based morphometry (VBM) standard and DARTEL registration with manual hippocampal volumetry in AD patients and cognitively normal older adults. Participants were 20 cognitively normal elderly subjects and 19 AD patients who met the criteria of probable AD according to NINCDS-ADRDA. Bilateral manual hippocampal volumetry was conducted alongside VBM of hippocampal regions-of-interest (ROIs) generated with standard and DARTEL registration using hippocampal masks and total intracranial volume normalization. All normalized hippocampal measurements showed significant reduction (20–30%; p < 0.001) in AD compared to controls. …Logistic regression analysis also showed significant effects (odds ratios ranged from 88.2% to 94.0%) of all normalized measurements in predicting AD incidence after adjusting for age, gender, and education. The overall prediction accuracies of manual RH and LH volumes, standard RH-ROI and LH-ROI VBM, DARTEL RH-ROI, and LH-ROI VBM were 87.2%, 84.6%, 87.2%, 76.9%, 87.2%, and 87.2%, respectively. As imaging biomarkers, VBM with DARTEL and standard registration have similarly high efficacies as manual hippocampal volumetry in discriminating AD from cognitively normal elderly adults. Show more

Keywords: Alzheimer's disease, ANALYZE 7.0 software, cognitively normal older adults, manual hippocampal volumetry, MRI, SPM5 software with DARTEL registration, 3.0 Tesla, VBM

DOI: 10.3233/JAD-2010-101659

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 655-664, 2011

Authors: Brouillette, Robert M. | Martin, Corby K. | Correa, John B. | Davis, Allison B. | Han, Hongmei | Johnson, William D. | Foil, Heather C. | Hymel, Aimee | Keller, Jeffrey N.

Article Type: Research Article

Abstract: There is an increasing need to develop new neuropsychometric tools sensitive enough to detect subtle declines in cognitive performance during normal aging, as well as to distinguish between normal aging and the earliest stages of dementia. In this study, we report our findings regarding a new confrontational naming test, the Memory for Names test. We conducted evaluations utilizing a cohort of 234 elderly participants who comprised a spectrum of cognitive function ranging from normal for age (Uniform Data Set Overall Appraisal = 2, Clinical Dementia Rating = 0) to demented (Clinical Dementia Rating = 1–2, Mini Mental Status Examination Total …Score <25). The Memory for Names test was found to measure the same cognitive construct as the Boston Naming Test. In conclusion, the Memory for Names test is a reliable and valid measure of age-related cognitive function that can discriminate between normal aging and mild cognitive impairment, and between mild cognitive impairment and dementia. Show more

Keywords: Alzheimer's disease, anomia, Boston naming, facial recognition, mild cognitive impairment

DOI: 10.3233/JAD-2011-101455

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 665-671, 2011

Authors: Cuevas, Magdalena E. | Haensgen, Henny | Sepúlveda, Fernando J. | Zegers, Gabriela | Roa, Jorge | Opazo, Carlos | Aguayo, Luis G.

Article Type: Research Article

Abstract: It is believed that amyloid-β peptide (Aβ), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Aβ1-40 on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Aβ1-40 peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Aβ were time and concentration dependent and were accompanied by increases in glutamatergic (0.8 ± 0.2 Hz to 2.9 ± …0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either Aβ or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro-convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of Aβ1-40 participates in the regulation of synaptic transmission increasing excitability and producing a pre epileptogenic state in hippocampal neurons. Show more

Keywords: Alzheimer disease, AMPA receptors, amyloid-β, bicuculline, epilepsy, GABA A receptors, NMDA receptors, synaptic plasticity

DOI: 10.3233/JAD-2011-091717

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 673-687, 2011

Authors: Orcholski, Mark E. | Zhang, Qiang | Bredesen, Dale E.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) has been implicated in Alzheimer's disease (AD) not only as a precursor of the amyloid-β peptide but also as a mediator of signal transduction. We recently identified novel mediators of AβPP signaling via interactions with Mint/X11 family proteins Mint1 and Mint3. These mediators include transcriptional co-activators Taz and Yap. Here we show that Taz and Yap also mediate signaling via the AβPP paralogues APLP1 and APLP2 through interactions with Mint1 and Mint3. APLP1 and APLP2 formed transcriptionally active triple protein complexes with the adaptor protein Mint3 and each of the transcriptional regulators Taz and Yap, …and complex formation was regulated by the γ-secretase cleavage of APLP1 and APLP2. The presence of Mint1 instead of Mint3 in the complex prevented its translocation to the nucleus. APLP1 displayed much lower transactivation levels compared to AβPP and APLP2. These results indicate that all three AβPP family members are capable of activating gene transcription via Mint3-Taz and Mint3-Yap. Show more

Keywords: Amyloid precursor-like protein (APLP), γ-secretase, gene transcription, triple protein complex

DOI: 10.3233/JAD-2010-101470

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 689-699, 2011