Journal of Alzheimer's Disease - Volume 34, issue 3

Authors: Wojda, Urszula | Kuznicki, Jacek

Article Type: Review Article

Abstract: Major breakthroughs are required to win the war against the increasing threat of Alzheimer's disease. Until now, however, despite enormous efforts and funds, effective therapies are lacking, and adequate models for drug validation are still unavailable. In this article, we review the available animal and cellular models of different features of human Alzheimer's disease and critically evaluate their usefulness for understanding the mechanisms of the disease. The majority of the presently used models are based on the amyloid-β and hyperphosphorylated tau hypothesis, which resembles features of familial Alzheimer's disease. Unfortunately, these models offer limited help for understanding the pathomechanisms of …the early stages of sporadic Alzheimer's disease. Thus, new models are needed to discover ways to treat or delay the onset of Alzheimer's disease, and we discuss the prospects for such desperately needed models, including human induced pluripotent stem cells and in silico brain models. Show more

Keywords: amyloid-β protein precursor, animal models, calcium homeostasis, cell cycle regulation, familial Alzheimer's disease, induced pluripotent stem cells, mitochondrial stress, presenilin 1, sporadic Alzheimer's disease, tau

DOI: 10.3233/JAD-121984

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 563-588, 2013

Authors: Li, Rena | Cui, Jie | Jothishankar, Balaji | Shen, Juliet | He, Ping | Shen, Yong

Article Type: Review Article

Abstract: Women experience dramatic changes in hormones, mood, and cognition through different periods of their reproductive lives, particularly during pregnancy and giving birth. While limited human studies of early pregnancy and motherhood showed alteration of cognitive function in later life, research conducted on rodents showed a persistent improvement of learning and memory performance in females with history of giving birth (primiparous or multiparous) compared to virgin controls (nulliparous). In this mini review, we will focus on the effect of early motherhood on cognitive function later in life, which would provide insight on how reproductive experiences influence women's health during aging.

Keywords: Cognition, gene regulation, motherhood, neurogenesis, pregnancy, steroids

DOI: 10.3233/JAD-122101

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 589-594, 2013

Authors: Merril, Carl R.

Article Type: Research Article

Abstract: The two major aspects of Alzheimer's disease (AD) that must be considered in a search for causative agents are its association with aging and its widespread epidemiology. While a number of agents have been identified, additional factors may play a role. An association with diphtheria toxin was suggested by observations that vaccinations may provide protective effects, and the observation that decreased proteins synthesis in cortical regions from AD patients is associated with modification of elongation factor 2, the target of diphtheria toxin. While protection against diphtheria toxin is provided by vaccination, the known decline in the immune system associated with …aging would result in a renewed sensitivity to the toxin. An association with diphtheria toxin would be consistent with the observations that the bacteria associated with the toxin, Corynebacterium diphtheria, is often found in the nasopharynx and an early symptom of AD is the loss of smell with a disease progression from the entorhinal cortex to the hippocampus and the neocortical areas. If diphtheria toxin is involved in sporadic AD, booster vaccinations given to elderly individuals might result in a decreased incidence of this disease. As booster DPT vaccinations are already recommended for individuals over 65, cognitive testing at the time of the booster and 5 years later, along with similar cognitive testing in age-matched individuals who decline vaccination, might provide an inexpensive method to investigate whether diphtheria toxin plays a role in AD and the efficacy of DPT booster vaccines for AD. Show more

Keywords: Alzheimer's disease, booster vaccine, diphtheria toxin, DPT vaccine, elongation factor 2, EF2, immune system, vaccination

DOI: 10.3233/JAD-121948

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 595-600, 2013

Authors: Tierney, Mary C. | Ryan, Joanne | Ancelin, Marie-Laure | Moineddin, Rahim | Rankin, Stephanie | Yao, Christie | MacLusky, Neil J.

Article Type: Research Article

Abstract: Menopausal changes in endogenous estrogen have been associated with memory decline. However, because earlier findings regarding the effects of lifelong estrogen exposure on memory have been inconsistent, our purpose was to investigate these effects in older postmenopausal women with a comprehensive battery of memory measures. Participants were 126 nondemented naturally postmenopausal women, not currently using hormone therapy (HT), 60 to 89 years of age, who showed normal to below average verbal memory performance on a screening test. Memory measures included tests of visual, verbal, and working memory. Regression analyses were performed with each memory measure as the outcome and length …of reproductive period (time between menarche and menopause) as the predictor, controlling for age, education, parity, duration of breastfeeding, previous HT and oral contraceptive use, as well as body mass index and depression. Longer reproductive period was significantly associated with better delayed visual memory, immediate and delayed verbal memory, and working memory. Previous HT use was also significantly associated with better verbal memory and delayed visual memory. Our findings suggest an enduring protective role of endogenous and exogenous estrogen on memory in older postmenopausal women with normal to below average verbal memory performance on a screening test. They also support our contention that the neuroprotective benefits of a longer reproductive period might only be evident after a longer period of postmenopausal estrogen deprivation, which would help clarify why such an association was not previously found in younger postmenopausal women. Replication is required with a larger sample representing a broader cross-section of the aging female population. Show more

Keywords: Estrogens, hormone replacement therapy, memory, reproductive period

DOI: 10.3233/JAD-122062

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 601-608, 2013

Authors: van Groen, Thomas | Kadish, Inga | Funke, Susanne Aileen | Bartnik, Dirk | Willbold, Dieter

Article Type: Research Article

Abstract: One of the characteristic pathological hallmarks of Alzheimer's disease (AD) is neuritic plaques. The sequence of events leading to deposition of amyloid-β (Aβ) peptides in plaques is not clear. Here we investigate the effects of D3, an Aβ oligomer directed D-enantiomeric peptide that was obtained from a mirror image phage display selection against monomeric or small oligomeric forms of Aβ42 , on Aβ deposition in aged AβPP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brains of these AD model mice for 8 weeks with FITC-labeled D3, and examined the subsequent changes in pathology and cognitive deficits. Initial …cognitive deficits are similar comparing control and D3-FITC-treated mice, but the treated mice show a significant improvement on the last day of testing. Further, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3-FITC, compared to the control mice. Finally, the amount of activated microglia and astrocytes surrounding Aβ deposits is dramatically reduced in the D3-FITC-treated mice. Our findings demonstrate that treatments with the high affinity Aβ42 oligomer binding D-enantiomeric peptide D3 significantly decrease Aβ deposits and the associated inflammatory response, and improve cognition even when applied only at late stages and high age. Together, this suggests that the treatment reduces the level of Aβ peptide in the brains of AβPP/PS1 mice, possibly by increasing Aβ outflow from the brain. In conclusion, treatments with this D-peptide have great potential to be successful in AD patients. Show more

Keywords: Age, Alzheimer's disease, amyloid, limbic system, mouse, plaques, treatment

DOI: 10.3233/JAD-121792

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 609-620, 2013

Authors: Won, Je-Seong | Kim, Jinsu | Annamalai, Balasubramaniam | Shunmugavel, Anandakumar | Singh, Inderjit | Singh, Avtar K.

Article Type: Research Article

Abstract: Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a …significant decrease in learning/memory performance and increases in brain levels of Aβ and vascular inflammatory markers. GSNO treatment (50 μg/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the Aβ levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NFκB and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial Aβ uptake. Additionally, GSNO treatment inhibited the β-secretase activity in primary rat neuron cell culture, thus reducing secretion of Aβ, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, bilateral common carotid artery occlusion, cerebral hypoperfusion, inflammation, S-nitrosylation, S-nitrosoglutathione

DOI: 10.3233/JAD-121786

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 621-635, 2013

Authors: Recuero, María | Munive, Victor A. | Sastre, Isabel | Aldudo, Jesús | Valdivieso, Fernando | Bullido, María J.

Article Type: Research Article

Abstract: Oxidative stress is an early event in the pathogenesis of Alzheimer's disease (AD). We previously reported that, in SK-N-MC cells, the xanthine/xanthine oxidase (X-XOD) free radical generating system regulates the metabolism/processing of the amyloid-β protein precursor (AβPP). Oxidative stress alters the two main cellular proteolytic machineries, the ubiquitin/proteasome (UPS) and the autophagy/lysosome systems, and recent studies have established connections between the malfunctioning of these and the pathogenesis of AD. The aim of the present work was to examine the involvement of these proteolytic systems in the regulation of AβPP metabolism by X-XOD. The proteasome inhibitor MG132 was found to accelerate …the metabolism/processing of AβPP promoted by X-XOD because it significantly enhances the secretion of α-secretase-cleaved soluble AβPP and also the levels of both carboxy-terminal fragments (CTFs) produced by α- and β-secretase. Further, MG132 modulated the intracellular accumulation of holo-AβPP and/or AβPP CTFs. This indicates that the X-XOD modulation of AβPP metabolism/processing involves the UPS pathway. With respect to the autophagy/lysosome pathway, the AβPP processing and intracellular location patterns induced by X-XOD treatment closely resembled those produced by the lysosome inhibitor ammonium chloride. The present results suggest that the regulation of AβPP metabolism/processing by mild oxidative stress requires UPS activity with a simultaneous reduction in that of the autophagy/lysosome system. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, free radicals, lysosome, metabolism, oxidative stress, proteasome

DOI: 10.3233/JAD-121510

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 637-647, 2013

Authors: Feng, Liang | Chong, Mei Sian | Lim, Wee Shiong | Lee, Tih Shih | Collinson, Simon L | Yap, Philip | Ng, Tze Pin

Article Type: Research Article

Abstract: Metabolic syndrome (MetS) is reported to be associated with cognitive decline and dementia, in particular vascular dementia. However, the evidence linking MetS to Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a precursor of AD, is inconsistent and limited. This study examined the association of MetS and its components with aMCI and how APOE-εe4 and younger age influenced this association. Participants with aMCI (n = 98) and cognitively normal controls (n = 802) were identified from baseline data in a second wave cohort of older subjects aged 55 and over in the Singapore Longitudinal Ageing Study-2 (SLAS-2) in 2009/2010. …The associations of MetS and its individual components with aMCI were analyzed using logistic regression controlling for age, gender, education, current smoking, alcohol drink, leisure time activities score, Geriatric Depression Scale score, APOE-ε4, and heart disease or stroke. The analysis was repeated for associations stratified by age and APOE-ε4 status. In multivariate analysis, MetS was associated with an elevated risk of aMCI (OR = 1.79; 95% CI 1.15–2.77). Among MetS components, central obesity showed a significant association with aMCI (OR = 1.77; 95% CI 1.11–2.82). The association between MetS and aMCI remained significant on repeated analysis among subjects free of heart disease and stroke. This association was particularly stronger among participants with APOE-ε4 allele (OR = 3.35; 95% CI, 1.03–10.85) and younger (<65 years) participants with APOE-ε4 (OR = 6.57; 95% CI, 1.03–41.74). MetS was found to be associated with aMCI, especially in individuals with APOE-ε4 at younger age in this middle-aged and older cohort. Show more

Keywords: Amnestic mild cognitive impairment, APOE-ε4, cognition, metabolic syndrome

DOI: 10.3233/JAD-121885

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 649-657, 2013

Authors: Moreno-Ramos, Teresa | Benito-León, Julián | Villarejo, Alberto | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Optical coherence tomography is a simple, high-resolution technique to quantify the thickness of retinal nerve fiber layer (RNFL). Previous studies have shown that degenerative changes occur in optic nerve fibers and are manifested as thinning of RNLF in patients with Alzheimer's disease (AD). However, there are no studies on the thickness of the RNLF in other types of dementia, such as dementia with Lewy bodies and dementia associated with Parkinson's disease. In this study, patients fulfilling diagnostic for AD (n = 10), dementia with Lewy bodies (n = 10), dementia associated with Parkinson's disease (n = 10), and cognitively normal …age-matched controls (n = 10) underwent optical coherence tomography examinations to measure RNLF thickness. There was a significant decrease in RNLF thickness in each type of dementia compared to the control group (Mann-Whitney test, all p < 0.001). Although patients with dementia with Lewy bodies may have a greater thinning than both patients with AD and dementia associated with Parkinson's disease, the differences were statistically nonsignificant (Kruskal-Wallis test, p = 0.525). The thickness of the RNLF correlated significantly (p < 0.001) with both the Mini-Mental State Examination and the Mattis Dementia Rating Scale scores in all types of dementia; that is to say, the greater the cognitive deterioration, the greater the reduction of thickness of the RNLF. The findings from this study show that retinal involvement measured by optical coherence tomography may also be present in non-AD dementias. Show more

Keywords: Alzheimer's disease, dementia, dementia associated with Parkinson's disease, dementia with Lewy bodies, optical coherence tomography

DOI: 10.3233/JAD-121975

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 659-664, 2013

Authors: Defrancesco, Michaela | Marksteiner, Josef | Deisenhammer, Eberhard | Kemmler, Georg | Djurdjevic, Tanja | Schocke, Michael

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may represent a prodromal stage of dementia and confers a particularly high annual risk of 10–15% for conversion to Alzheimer's disease (AD). Recent findings suggest that white matter lesion pathology (WML) can negatively influence conversion from MCI to AD. In this study, we examined the predictive value of neuropsychological test results and WML pathology on conversion of MCI to AD. Retrospective neuropsychological and magnetic resonance imaging data were collected for MCI patients seen at the University Clinic of Innsbruck between 2005 and 2011. WML were visually rated using the Fazekas and Scheltens scales. Of the 60 …subjects, 31 converted to AD during a follow-up of 18.3 ± 7.4 months and 29 remained stable. Orientation, MMSE score, word list learning and recall, visual memory, and naming scores were significantly lower in MCI patients converting to AD than in non-converters. Converters had significantly higher Fazekas scores and more WML in periventricular regions. Periventricular WML were negatively associated with psychomotor speed, and subcortical WML were negatively correlated with visual memory at baseline in all MCI patients. Low scores in orientation and verbal delayed recall were predictors of progression from MCI to AD. Periventricular WML correlate with lower cognitive function in patients with MCI. However, deficits in orientation and verbal memory, but not vascular changes, turned out as predictive for conversion from MCI to AD. Consequently, a higher WML burden may represent a serious risk factor but not an early symptom for the imminent conversion to AD. Show more

Keywords: Dementia, magnetic resonance imaging, microvascular changes, visual rating

DOI: 10.3233/JAD-122095

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 665-672, 2013