Journal of Alzheimer's Disease - Volume 21, issue 1

Authors: Hensley, Kenneth

Article Type: Review Article

Abstract: The concept of neuroinflammation has evolved over the past two decades from an initially controversial viewpoint to its present status as a generally accepted idea whose mechanisms and consequences are still actively under research and debate, particularly with regard to Alzheimer's disease (AD). This review summarizes the current status of neuroinflammation research as it specifically relates to AD. Neuroinflammation is discussed mechanistically with emphasis on the role of redox signal transduction linked to the activation of central nervous system-relevant innate immune pathways. Redox signaling is presented both as a causal factor and a consequence of sustained neuroinflammation. Functional relationships are …discussed that connect distinct neuroinflammatory components such as cytokines, eicosanoids, classic AD pathology (amyloid plaques and neurofibrillary tangles), and the recently emergent notion of "damage-associated molecular patterns". The interaction of these paracrine factors likely can produce positive as well as negative effects on the AD brain, ranging from plaque clearance by microglia in the short term to glial dysfunction and neuronal compromise if the neuroinflammation is chronically sustained and unmitigated. Recent disappointments in AD clinical trials of anti-inflammatory drugs are discussed with reference to possible explanations and potential avenues for future pharmacological approaches to the disease. Show more

Keywords: Alzheimer's disease, cytokines, damage-associated molecular patterns (DAMPs), eicosanoids, neuroinflammation, redox signaling

DOI: 10.3233/JAD-2010-1414

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 1-14, 2010

Authors: Kirby, Elizabeth | Bandelow, Stephan | Hogervorst, Eef

Article Type: Review Article

Abstract: Visual impairment is a common symptom of Alzheimer's disease (AD). Recent studies have demonstrated the potential of visual interventions to improve the functioning of AD patients. Therefore, clarification of the profile of visual deficits in AD and possible mechanisms underlying these deficits are needed. This review focuses on three areas as mechanisms for the visual impairment in AD: 1) the broad-band pathway deficit; 2) glaucoma; and 3) the relative dysfunction of the ventral and dorsal streams of vision. While much research has been produced with regard to these areas, methodological flaws and lack of continuity between studies has led to …conflicting findings. Nevertheless, recent imaging research suggests that the loss of retinal ganglion cells in AD may play an important role in the visual deficit in AD. This review looks to critically evaluate current research and highlight the need to investigate recent significant findings in primary vision research in understanding the impairment of vision in AD. Show more

Keywords: Alzheimer's disease, broad-band channel, cognition, contrast sensitivity, dementia, dorsal stream, glaucoma, ventral stream, vision, visual cortex

DOI: 10.3233/JAD-2010-080785

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 15-34, 2010

Authors: Iurescia, Sandra | Fioretti, Daniela | Mangialasche, Francesca | Rinaldi, Monica

Article Type: Review Article

Abstract: Apolipoprotein E (ApoE) plays a key role in lipid transport in the plasma and in the central nervous system through its interaction with members of the low-density lipoprotein receptor family. The three common isoforms of ApoE (ApoE2, ApoE3, and ApoE4) differ in their ability to perform neuronal maintenance and repair functions and differentially affect the risk of developing neurodegenerative disorders. The ApoE4 isoform is a strong genetic risk factor for Alzheimer's disease. Up-to-date knowledge about the structural and biophysical features of ApoE4 shed light on the molecular basis underlying the isoform-specific pathogenic role of ApoE4 and its contribution to AD …pathology through several different mechanisms. ApoE4 impacts on amyloid-β (Aβ) production, Aβ clearance, Aβ fibrillation, and tangle formation as well as on mitochondrial functions leading to neuronal toxicity and synaptic damage. This review summarizes the pathological cross talk between ApoE and Aβ peptide in Alzheimer's disease. Lastly, we examine emerging gene-based therapeutic approaches encompassing the use of ApoE and their potential opportunities to preventing or treating Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, gene-based therapy

DOI: 10.3233/JAD-2010-100009

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 35-48, 2010

Authors: Chan, Amy | Shea, Thomas B.

Article Type: Research Article

Abstract: The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide …sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition. Show more

Keywords: Alzheimer's disease, apolipoprotein E, diet, nutritional deficiency, oxidative stresss

DOI: 10.3233/JAD-2010-100060

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 49-55, 2010

Authors: Frisardi, Vincenza | Solfrizzi, Vincenzo | Capurso, Cristiano | Imbimbo, Bruno P. | Vendemiale, Gianluigi | Seripa, Davide | Pilotto, Alberto | Panza, Francesco

Article Type: Research Article

Abstract: Cumulative evidence suggests that metabolic syndrome (MetS) may be important in the development of mild cognitive impairment, vascular dementia, and Alzheimer's disease (AD). As such, these patients might be described as having "metabolic-cognitive syndrome" – MetS plus cognitive impairment of degenerative or vascular origin. While peripheral insulin resistance appears to be of primary pathophysiological importance in MetS, the definitions of MetS and its components do not include any reference to insulin resistance or hyperinsulinemia. In the present article, we discuss the role of these factors in the development of cognitive decline and dementia, including underlying mechanisms that influence amyloid-β (Aβ) …peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD. In AD, an age-related desynchronization of biological systems results, involving stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates that precipitates an insulin resistant brain state (IRBS) with decreased glucose/energy metabolism and the increased formation of hyperphosphorylated tau protein and Aβ. Unfortunately, it is very difficult to include the measurement of peripheral insulin resistance in the current MetS criteria or the identification of IRBS for the metabolic-cognitive syndrome. However, since inflammation has been suggested among the MetS components, we propose IRBS as an additional feature of the metabolic-cognitive syndrome to also identify a molecular profile in patients at high risk of developing predementia or dementia syndromes. Show more

Keywords: Amyloid-β peptide metabolism, hyperinsulinemia, hyperphosphorylated tau protein, insulin resistance, insulin resistant brain state, metabolic syndrome, type 2 diabetes mellitus

DOI: 10.3233/JAD-2010-100015

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 57-63, 2010

Authors: Chang, Po-Yuan | Lu, Shao-Chun | Chen, Chu-Huang

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-100144

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 65-66, 2010

Authors: Herz, William C. | de Peralta, Jesus I. Grave

Article Type: Article Commentary

Keywords: Alzheimer's disease, diabetes mellitus, fertilizer, incidence, nitrates, nitrites, nitrosamines

DOI: 10.3233/JAD-2010-091702

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 67-70, 2010

Authors: de la Monte, Suzanne M.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-091703

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 71-73, 2010

Authors: Nelson, Peter T. | Wang, Wang-Xia

Article Type: Short Communication

Abstract: MiR-107 is a microRNA (miRNA) that we reported previously to have decreased expression in the temporal cortical gray matter early in the progression of Alzheimer's disease (AD). Here we study a new group of well-characterized human temporal cortex samples (N=19). MiR-107 expression was assessed, normalized to miR-124 and let-7a. Correlation was observed between decreased miR-107 expression and increased neuritic plaque counts (P< 0.05) and neurofibrillary tangle counts (P< 0.02) in adjacent brain tissue. Adjusted miR-107 and BACE1 mRNA levels tended to correlate negatively (trend with regression P< 0.07). In sum, miR-107 expression tends to be lower relative to other miRNAs …as AD progresses. Show more

Keywords: Amyloid, metabolism, neurodegeneration, noncoding, RTqPCR, tau

DOI: 10.3233/JAD-2010-091603

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 75-79, 2010

Authors: Ikeda, Tokuhei | Ono, Kenjiro | Elashoff, David | Condron, Margaret M. | Noguchi-Shinohara, Moeko | Yoshita, Mitsuhiro | Teplow, David B. | Yamada, Masahito

Article Type: Short Communication

Abstract: Oligomers of the amyloid β-protein (Aβ) play an important role in Alzheimer's disease (AD). We hypothesized that AD patients have a central nervous system environment that promotes Aβ oligomerization. We investigated the effect of cerebrospinal fluid (CSF) from 33 patients with AD and 33 age-matched, non-demented controls on oligomerization of Aβ1-40 and Aβ1-42 using the technique of photo-induced cross-linking of unmodified proteins. CSF inhibited oligomerization of both Aβ1-40 and Aβ1-42 . This inhibitory effect was significantly weaker in AD patients than in non-demented controls. Our results indicate that AD patients have a CSF environment favorable for Aβ …oligomerization. Show more

Keywords: Alzheimer's disease, amyloid β-protein, central nervous system, oligomer, oligomerization, photo-induced cross-linking of unmodified proteins

DOI: 10.3233/JAD-2010-100075

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 81-86, 2010