Journal of Alzheimer's Disease - Volume 29, issue 2

Authors: Lizard, Gérard | Rouaud, Olivier | Demarquoy, Jean | Cherkaoui-Malki, Mustapha | Iuliano, Luigi

Article Type: Review Article

Abstract: In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in …neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed. Show more

Keywords: Alzheimer's disease, carnitine-dependent enzymes, dementia, DHA, peroxisome, plasmalogen

DOI: 10.3233/JAD-2011-111163

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 241-254, 2012

Authors: Walton, J.R.

Article Type: Review Article

Abstract: Most humans living in industrialized societies are routinely exposed to bioavailable aluminum salts in the form of additives—in commercially-prepared foods, alum-clarified drinking water, certain pharmaceuticals, sunscreens, and other topical applications. Minute amounts of this aluminum are absorbed into the circulation. Trace aluminum levels cross the blood-brain barrier and progressively accumulate in large pyramidal neurons of the hippocampus, cortex, and other brain regions vulnerable in Alzheimer's disease. More aluminum enters the brain than leaves, resulting in a net increase in intraneuronal aluminum with advancing age. Aluminum is responsible for two main types of toxic damage in cells. As a pro-oxidant, aluminum …causes oxidative damage both on its own and in synergy with iron. Aluminum also competes with, and substitutes for, essential metals—primarily Mg2+ , iron and Ca2+ ions—in or on proteins and their co-factors. The author hypothesizes that intraneuronal aluminum interferes with Ca2+ metabolism in the aged brain and describes a way to test this hypothesis. This paper reviews: 1) major changes that occur in brain Ca2+ homeostasis and Ca2+ signaling, subtly with aging and more overtly in Alzheimer's disease; and 2) evidence from the scientific literature that aluminum causes these same changes in neurons. Show more

Keywords: Aluminum, Alzheimer's disease, Ca2+-ATPase, calcium, calmodulin, G proteins, magnesium, neurotoxicant, oxidative damage, protein kinase C, signal transduction

DOI: 10.3233/JAD-2011-111712

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 255-273, 2012

Authors: Korczyn, Amos D.

Article Type: Research Article

Abstract: There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, just like hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, …like apoptosis or amyloid-β accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for “senile dementia of the Alzheimer type”, some genetic but most environmental and therefore modifiable. Thus, a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age. Show more

Keywords: Alzheimer's disease, amyloid-β, drug studies, senile dementia therapy

DOI: 10.3233/JAD-2011-110359

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 275-282, 2012

Authors: Deci, Stephen | Lemieux, Susan K. | Smith-Bell, Carrie A. | Sparks, D. Larry | Schreurs, Bernard G.

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease is a significant increase in ventricular volume. To date we and others have shown that a cholesterol-fed rabbit model of Alzheimer's disease displays as many as fourteen different pathological markers of Alzheimer's disease including amyloid-β accumulation, thioflavin-S staining, blood brain barrier breach, microglia activation, cerebrovasculature changes, and alterations in learning and memory. Using structural magnetic resonance imaging at 3T, we now report that cholesterol-fed rabbits also show a significant increase in ventricular volume following 10 weeks on a diet of 2% cholesterol. The increase in volume is attributable in large part to increases …in the size of the third ventricle. These changes are accompanied by significant increases in the number of amyloid-β immuno-positive cells in the cortex and hippocampus. Increases in the number of amyloid-β neurons in the cortex also occurred with the addition of 0.24 ppm copper to the drinking water. Together with a list of other pathological markers, the current results add further validity to the value of the cholesterol-fed rabbit as a non-transgenic animal model of Alzheimer's disease. Show more

Keywords: Amyloid-β, animal model, copper, lateral ventricle, MRI, third ventricle

DOI: 10.3233/JAD-2011-111415

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 283-292, 2012

Authors: Krantic, Slavica | Isorce, Nathalie | Mechawar, Naguib | Davoli, Maria Antonietta | Vignault, Erika | Albuquerque, Marilia | Chabot, Jean-Guy | Moyse, Emmanuel | Chauvin, Jean-Pierre | Aubert, Isabelle | McLaurin, JoAnne | Quirion, Rémi

Article Type: Research Article

Abstract: The relevance of γ-amino-butyric acid (GABA)-ergic dysfunctions in the pathology of Alzheimer's disease (AD) remains a matter of debate. In the present study, we characterized the toxicity of amyloid-β (Aβ) on hippocampal GABAergic neurons both in vivo and in vitro. In the TgCRND8 mouse model of AD, we found a significant decrease in the number of hippocampal neurons immunoreactive for glutamate decarboxylase 67 (GAD67), the enzyme synthesizing GABA. This decrease, which was specific for hippocampal CA1-3 fields, was observed at 6 months of age, long after the overproduction of soluble Aβ42 (between 2 and 4 months) and accumulation of …insoluble Aβ into amyloid plaques (between 4 and 6 months). In vitro, neurotoxicity was observed in primary hippocampal cultures 72 h following the addition of Aβ42 solutions containing a mixture of soluble oligomers. Taken together, our results suggest that when cultured and exposed to Aβ in vitro, GABAergic neurons are susceptible to Aβ42 neurotoxicity. However, in TgCRND8 mice, the number of GABAergic neurons is not altered up to 6 months, in spite of the massive Aβ load. Combined with the previously reported increased sensitivity to seizures observed in younger (1.5–2 month-old) TgCRND8 mice, it is likely that Aβ toxicity leads to GABAergic neuron dysfunction prior to their losses at a later stage. Show more

Keywords: Alzheimer's disease, amyloid beta-protein, GABAergic neurons, hippocampus, neuronal cell death, primary cell culture, TgCRND8 mice

DOI: 10.3233/JAD-2011-110830

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 293-308, 2012

Authors: Stephan, Blossom C.M. | Matthews, Fiona E. | Ma, Brandy | Muniz, Graciela | Hunter, Sally | Davis, Daniel | McKeith, Ian G. | Foster, Gill | Ince, Paul G. | Brayne, Carol | The Medical Research Council Cognitive Function and Ageing Neuropathology Study

Article Type: Research Article

Abstract: The state between aging with no cognitive impairment and dementia has become a major focus for intervention. The neuropathological and neurobiological correlates of this intermediate state are therefore of considerable interest, particularly from population representative samples. Here we investigate the neuropathological profile associated with different cognitive ability levels measured using strata defined by Mini Mental State Examination (MMSE) scores. One hundred and fifty one individuals were stratified into three cognitive groups including: non-, mildly, and moderately impaired at death. Alzheimer's disease, atrophy, and vascular pathologies were investigated. Mild impairment was associated with an increased risk of vascular pathologies including small …vessel disease and lacunes. In contrast, the moderately impaired group showed a more extensive pattern of pathology, including tangles and neuritic plaques (entorhinal/hippocampus), atrophy (cortical and hippocampal), and vascular disease (small vessel disease, lacunes, and infarcts). In a population-based sample of older people, MMSE score defined strata are associated with multiple pathologies. The profile of AD and vascular changes becomes more complex with increased cognitive impairment and these changes are likely to constitute a major substrate for age associated cognitive impairment. The results highlight the need for rigorous investigation of both neurodegenerative and vascular risks factors in old age. Show more

Keywords: Aging, Alzheimer's disease, cognitive impairment, neuropathology, vascular pathology

DOI: 10.3233/JAD-2011-110518

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 309-318, 2012

Authors: van Rossum, Ineke A. | Visser, Pieter Jelle | Knol, Dirk L. | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Barkhof, Frederik | Blankenstein, Marinus A. | Scheltens, Philip

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and …lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42 , APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, clinical progression, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2011-111694

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 319-327, 2012

Authors: Liu, Zhiheng | Zhu, Haihao | Fang, Guang Guang | Walsh, Kathryn | Mwamburi, Mkaya | Wolozin, Benjamin | Abdul-Hay, Samer O. | Ikezu, Tsuneya | Leissring, Malcolm A. | Qiu, Wei Qiao

Article Type: Research Article

Abstract: Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and …further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD. Show more

Keywords: Aβ degradation, Alzheimer's disease, angiotensin converting enzyme, insulin degrading enzyme, protease, serum

DOI: 10.3233/JAD-2011-111472

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 329-340, 2012

Authors: Mueller, Claudius | Schrag, Matthew | Crofton, Andrew | Stolte, Jens | Muckenthaler, Martina U. | Magaki, Shino | Kirsch, Wolff

Article Type: Research Article

Abstract: Alzheimer's disease (AD) brain is marked by severe neuronal death which has been partly attributed to increased oxidative stress. The pathophysiology accounting for this free radical injury is not well-delineated at this point, but one hypothesis is that a derangement in transition metal metabolism contributes to the process. We tested the hypothesis that peripheral derangement of transition metal metabolism is present early in the dementing process. We analyzed non-heme iron and copper levels in serum from subjects with normal cognition, mild cognitive impairment, and early stage senile dementia and followed these subjects over 5 years. An increase in the ratio …of serum copper to non-heme iron levels predicted which subjects with mild cognitive impairment would progress to dementia versus those that would remain cognitively stable. This increase did not correlate with changes in expression of iron regulatory protein 2 or selected downstream targets in peripheral lymphocytes. A cDNA-based microarray (IronChip) containing genes relevant to iron and copper metabolism was used to assess transition metal metabolism in circulating lymphocytes from cognitively normal and demented subjects. No gene was identified as being dysregulated more than 2-fold, and verification using quantitative RT-PCR demonstrated no significant changes in expression for ALAS2, FOS, and CTR1. The increased ratio of serum copper to serum iron prior to dementia has potential as a biomarker for cognitive decline and mirrors other changes in serum previously reported by others, but iron and copper metabolism pathways appear to be broadly unaffected in peripheral blood in AD. Show more

Keywords: ALAS, CTR1, FOS, IronChip, oxidative stress, biomarker, iron, copper, Alzheimer's disease

DOI: 10.3233/JAD-2011-111841

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 341-350, 2012

Authors: Lang, Haijing | Huang, Xudong | Yang, Yongliang

Article Type: Research Article

Abstract: β-secretase (BACE-1), an enzyme critical in the process of amyloid-β (Aβ) peptides deposition in human brain, is closely associated with the onset and progression of Alzheimer's disease (AD). A strong need exists, therefore, to identify molecular imaging probes homing at BACE-1 for use with positron emission tomography (PET) that is recognized as an effective tool for detecting AD. Through this imaging, an early diagnosis of AD could be made. Herein, to identify suitable molecular probes for use with PET, we searched the Molecular Imaging and Contrast Agent Database (MICAD), an online database warehousing scientific information regarding molecular imaging and contrast …agents, and applied a virtual screening approach against the different confirmations of BACE-1 obtained from the World Wide Protein Database. The lack of considering receptor flexibility is a key drawback in virtual screening for drug discovery. Therefore, we incorporated protein flexibility into the virtual screening by using an ensemble of 143 experimental BACE-1 structures derived from the Protein Data Bank. Finally, the best performing affinity was recorded and used in the ranking of each ligand. To the best of our knowledge, this is the first virtual screening approach used to identify four new molecular probes that could target BACE-1 with favorable affinity, a discovery that can lead to the development of new PET probes for the early detection and therapy of AD. However, the actual utility of these probes can only be ascertained after in vitro and in vivo investigations. Show more

Keywords: Alzheimer's disease, BACE, MICAD, PET probes, protein flexibility, receptor ensemble, virtual screening

DOI: 10.3233/JAD-2011-111787

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 351-359, 2012