Journal of Alzheimer's Disease - Volume 27, issue 1

Authors: Pac-Soo, Chen | Lloyd, Dafydd G. | Vizcaychipi, Marcela P. | Ma, Daqing

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease commonly seen in the elderly and is characterized by progressive cognitive and physical decline. Current understanding of AD pathogenesis revolves around amyloid-β peptide (Aβ), a product of the sequential proteolytic cleavage of the transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretase, enzymes found predominantly in the cholesterol rich micro domains of the cell membrane. Several risk factors for AD are associated with cholesterol metabolism, including dyslipidaemia, coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability and show a favorable side effect profile overall. By competitive inhibition …of hydroxymethyl co-enzyme A-reductase, statins reduce the production of cholesterol and isoprenoid intermediates including geranylgeranyl and farnesyl pyrophosphate. These isoprenoids modify recently translated proteins such as small GTPase molecules that are essential in numerous cell-signaling pathways, including vesicular trafficking and inflammation. In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function and by reducing neuroinflammation. Furthermore, epidemiological studies suggest that statins may reduce the incidence of AD. Consequently, statins, secondary of their anti-hypercholesterolaemic, plieotropic and anti-inflammatory effects, are being investigated for a potential therapeutic role. This review will discuss evidence for the role of statins in the treatment and prevention of AD neurodegeneration. Show more

Keywords: Alzheimer's disease, cholesterol, inflammation, microglial activation, statin

DOI: 10.3233/JAD-2011-110524

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 1-10, 2011

Authors: Didic, Mira | Barbeau, Emmanuel J. | Felician, Olivier | Tramoni, Eve | Guedj, Eric | Poncet, Michel | Ceccaldi, Mathieu

Article Type: Research Article

Abstract: Diagnosis of Alzheimer's disease (AD) in its earliest stages becomes increasingly important as disease modifying agents are being developed. In this area of research, many clinical and neuroimaging studies focus on markers of hippocampal dysfunction. However, during the “transentorhinal stage” of AD, neurofibrillary tangles (NFT), related to tau protein pathology, develop in the anterior subhippocampal (perirhinal/entorhinal) cortex before the hippocampus. NFT are tightly correlated with clinical symptoms. Therefore, an accurate understanding of the behavioral correlate of transentorhinal dysfunction could critically contribute to the early diagnosis of the disease. Recent findings from studies in animals and human brain-damaged patients suggest that …the anterior subhippocampal region, functionally integrated into an anterior mesiotemporal network, is involved in object based context-free memory. In this article, we evaluate the hypothesis according to which tau deposition in the anterior subhippocampal region during the earliest stages of the most common form of AD, with predominant MTL dysfunction, will lead to dysfunction of neural networks implicated in context-free memory. We challenge the view that impaired episodic memory is the hallmark of early AD. Instead, a model that integrates the localization and temporal sequence of NFT within the mesial temporal lobe (MTL) is proposed. Paralleling the development of NFT in anterior subhippocampal areas, impaired context-free, object-based, memory could be the first detectable sign in AD. In a subsequent, “hippocampal” stage, context-rich, episodic and spatial memory, becomes altered as well. The question as to the “episodic” nature of “episodic memory tasks” is also addressed. Show more

Keywords: Alzheimer's disease, amnesia, entorhinal cortex, hippocampus, memory, mesial temporal lobe, perirhinal cortex

DOI: 10.3233/JAD-2011-110557

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 11-22, 2011

Authors: Kou, Jinghong | Kim, HongDuck | Pattanayak, Abhinandan | Song, Min | Lim, Jeong-Eun | Taguchi, Hiroaki | Paul, Sudhir | Cirrito, John R. | Ponnazhagan, Selvarangan | Fukuchi, Ken-ichiro

Article Type: Research Article

Abstract: Accumulation of amyloid-β protein (Aβ) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Here, we evaluated the efficacy and safety of anti-Aβ single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Aβ deposits in an AD mouse model (TgAβPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via …rAAV1 or rAAV5, while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAβPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAβPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Aβ deposits reduced in the hippocampus. Aβ42 levels in cerebrospinal fluid (CSF) tended to increase and the Aβ40 : 42 ratio decreased in CSF, suggesting that Aβ42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Aβ, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Aβ immunotherapy is applied. Show more

Keywords: Adeno-associated virus, Alzheimer's disease, amyloid, cerebral hemorrhage, immunotherapy, single-chain antibodies

DOI: 10.3233/JAD-2011-110230

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 23-38, 2011

Authors: Pérès, Karine | Helmer, Catherine | Amieva, Hélène | Matharan, Fanny | Carcaillon, Laure | Jacqmin-Gadda, Hélène | Auriacombe, Sophie | Orgogozo, Jean-Marc | Barberger-Gateau, Pascale | Dartigues, Jean-François

Article Type: Research Article

Abstract: Subjective memory complaint (SMC) and restriction in cognitively-complex activities of daily living (such as instrumental ADL) are two early symptoms observed in the prodromal phase of dementia and may represent useful alarm signals for general practitioners for an increased risk of subsequent dementia. We here studied in a large population-based epidemiological cohort on aging, the risk of dementia associated with SMC and restriction in IADL, with a specific interest in a potential interaction by gender. The sample included 2,901 subjects, aged 65 years and over, initially free of dementia and followed over 15 years. After controlling for education, marital status, …depressive symptomatology, and global cognition (MMSE), IADL-restriction was associated with an increased risk of dementia only in men (HR = 2.04, 1.27 to 3.29), whereas SMC was not (p = 0.95). The reverse was observed in females, in whom SMC almost doubled the risk of dementia (1.48 to 2.41), with no association with IADL-restriction (p = 0.74). Finally, we distinguished the risk of dementia at short-term (in the first 5 years), mid-term (between 5 and 10 years), and long-term (between 10 and 15 years). In women, SMC was significantly associated with greater risk of dementia whatever the risk period considered, even at longer term (HR = 1.61, p = 0.0216), whereas in men the increased risk was also observed with IADL-restriction and only in the first 5 years. To conclude, women would report the first symptoms very early in the process by SMC, whereas men would tend to later report their difficulties and only in terms of IADL-restriction. Show more

Keywords: Activities of daily living, aged, cohort studies, dementia, memory disorders

DOI: 10.3233/JAD-2011-110428

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 39-47, 2011

Authors: Davies, Sean S. | Bodine, Chris | Matafonova, Elena | Pantazides, Brooke G. | Bernoud-Hubac, Nathalie | Harrison, Fiona E. | Olson, Sandra J. | Montine, Thomas J. | Amarnath, Venkataraman | Roberts II, L. Jackson

Article Type: Research Article

Abstract: Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive γ-ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of γ-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of γ-ketoaldehyde protein adducts in the cerebellum were not …different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available γ-ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12–14 month old ApoE4 mice. These findings suggest that γ-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether γ-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD. Show more

Keywords: Aldehydes, Alzheimer's disease, inflammation, isolevuglandin, oxidative stress, salicylamine, working memory

DOI: 10.3233/JAD-2011-102118

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 49-59, 2011

Authors: Viana, Ricardo J.S. | Steer, Clifford J. | Rodrigues, Cecília M.P.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide-induced neurotoxicity is typically associated with cell death through mechanisms not entirely understood. Here, we investigated stress signaling events triggered by soluble Aβ in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ induced nuclear fragmentation that was prevented by pre-treatment with the antiapoptotic bile acid tauroursodeoxycholic acid (TUDCA). In addition, Aβ exposure triggered an early signaling response by the endoplasmic reticulum (ER) and caspase-12-mediated apoptosis, which, however, was independent of the ER-stress pathway. Furthermore, ER stress markers, including GRP94, ATF-6α, CHOP, and eIF2α, were strongly downregulated by Aβ, independent of protein degradation, and partially …restored by TUDCA. Calpain inhibition prevented caspase-12 activation and reduced levels of ATF-6α. Importantly, Aβ-induced GRP94 downregulation was related to protein secretion and partially rescued through inhibition of the secretory pathway by geldanamycin and brefeldin. In conclusion, we showed that the ER is a proximal stress sensor for soluble Aβ-induced toxicity, resulting in caspase-12 activation and cell death in PC12 neuronal cells. Moreover, ER chaperone GRP94 secretion was associated with Aβ-induced apoptotic signaling. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway is likely to provide new perspectives for modulation of amyloid-induced apoptosis. Show more

Keywords: Amyloid-β, ATF-6α, caspase-12, endoplasmic reticulum, GRP94, tauroursodeoxycholic acid

DOI: 10.3233/JAD-2011-100395

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 61-73, 2011

Authors: Alikhani, Nyosha | Guo, Lan | Yan, Shiqiang | Du, Heng | Pinho, Catarina Moreira | Chen, John Xi | Glaser, Elzbieta | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. …We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD. Show more

Keywords: Mitochondrial amyloid-β, mitochondrial function, oxidative stress, presequence protease (PreP), proteolysis

DOI: 10.3233/JAD-2011-101716

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 75-87, 2011

Authors: Yin, Jun-xiang | Turner, Gregory H. | Lin, Hao-jie | Coons, Stephen W. | Shi, Jiong

Article Type: Research Article

Abstract: Apolipoprotein E ε4 (ApoE4) has been implicated as a potential genetic risk factor for dementia. In this study, we investigate the effect of ApoE4 on learning and memory, changes in brain volume and neuroinflammatory responses in brain of ApoE4 transgenic mice. Four groups of male mice with ApoE4 and age-matched wild type (WT) (6-, 12-, 18- and 24-month) were studied. Spatial learning and retaining of mice was examined in the Morris Water Maze (MWM). Changes in brain volume (including the whole brain, hippocampus, cortex, total ventricles, and caudate putamen) were assessed by using 7T small animal MRI. Neuroinflammatory responses were …analyzed by measuring the levels of microglia (Iba-1), iNOS, TNFα, and IL-6 quantitatively. In the MWM, ApoE4 mice showed longer escape latency (p < 0.05) and swim distance (p < 0.05) at age 12 month and older, comparing with the WT mice. They also demonstrated poor memory retention in the probe test (p < 0.05). Brain atrophy was significant in ApoE4 mice than age-matched WT mice (18 months: 0.079 ± 0.004 versus 0.086 ± 0.003, p = 0.018; and 24 months: 0.074 ± 0.005 versus 0.084 ± 0.006, p = 0.008). The expression of Iba-1, iNOS, and TNFα in hippocampus and cortex were significantly higher in ApoE4 mice than in WT mice at 12 months and older. These data suggest that ApoE4 plays an important role in learning and memory impairment. These deficits are associated with neuroinflammatory responses that may in turn lead to atrophy in hippocampus and cortex. Show more

Keywords: Aging, apolipoprotein E, cognition, hippocampus

DOI: 10.3233/JAD-2011-110479

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 89-98, 2011

Authors: Fisher, Yair | Nemirovsky, Anna | Baron, Rona | Monsonego, Alon

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in the brain is one of the hallmarks of Alzheimer's disease (AD). T-cell entry into vascular and parenchymal brain areas loaded with Aβ has been observed with both beneficial as well as detrimental effects. Using a new AD mouse model, we studied the molecular mechanisms allowing CD4 T cells to specifically target Aβ-loaded brain areas. We observed that following Aβ immunization, CD11c+ dendritic cells (DCs) and CD4 T cells occurred primarily in the perivascular and leptomeningial spaces of cerebral vessels deposited with Aβ. CD11c+ cells expressed high levels of the DC maturation markers DEC-205, MHC …class II and CD86. Notably, the majority of cerebral blood vessels were found adjacent to Aβ plaques, expressing high levels of the ICAM-1 and VCAM-1 adhesion molecules. We propose that the drainage of Aβ to the leptomeningeal and perivascular spaces and its deposition there provide the antigenic source for DCs to stimulate Aβ-specific T cells on their way to target amyloid plaques within the brain tissue. Show more

Keywords: Alzheimer's disease, amyloid-β, dendritic cells, T cells

DOI: 10.3233/JAD-2011-102034

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 99-111, 2011

Authors: Yang, Hongqian | Lyutvinskiy, Yaroslav | Soininen, Hilkka | Zubarev, Roman A.

Article Type: Research Article

Abstract: Increased levels of isoaspartyl residues (isoAsp) have previously been found in proteins of Alzheimer's disease (AD) brains and in blood proteins of patients suffering from uremia, the disease sharing common pathological features with AD. One can hypothesize that higher levels of isoAsp should be present in blood proteins of AD patients. Also, because of higher AD prevalence in females, they can be expected to have higher level of isoAsp than males. Here we modified our recently developed proteome-wide isoAsp analysis approach for testing these hypotheses. Eight blood plasma samples pooled from 218 individuals suffering from either mild cognitive impairment (MCI) …or AD were analyzed by tandem mass spectrometry using electron transfer dissociation. Based on specific fragmentation pattern of isoAsp, the healthy controls were found to contain lower level of isoAsp compared with age-matched MCI and AD patients (p = 0.03). This result was further validated (p = 0.05) by 96 individual sample analyses, giving the combined value of p ≈ 0.01. Female pooled samples were found to contain higher level of isoAsp than male in both pooled and individual samples, with overall p ≈ 0.01. These findings verify the above hypotheses, and provide protein candidates for further investigation of the link between isoAsp and AD. Show more

Keywords: Aspartyl isomerization, blood plasma, electron capture dissociation, label-free quantification, tandem mass spectrometry

DOI: 10.3233/JAD-2011-110626

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 113-118, 2011