Journal of Alzheimer's Disease - Volume 20, issue 2

Authors: Daulatzai, Mak Adam

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive, neurodegenerative brain disease of the elderly characterized by memory loss, cognition, and behavioral abnormalities. Aging is the single most important risk factor and there is no proven therapy. Aging invariably decreases sensory stimuli and impacts on the thalamocortical system and its connectivity to key brain regions. Memory dysfunction in senescence and early AD, a function of acetylcholine decrease, is accompanied with dysfunctional basal forebrain, parietal, prefrontal, and entorhinal cortices, and indeed hippocampus. Cholinergic neurotransmission protects neurons from amyloid-β production and its toxicity, while cholinergic depletion enhances both. Available data on sleep disordered breathing and …genioglossus dysfunction throw light on possible pathogenetic events leading to hypoxemia. Memory disturbances in normal elderly and early AD patients are intimately related to hypoxia, a reduction in blood supply, and glucose hypometabolism in the hippocampus and a number of key brain areas. The current hypothesis on memory impairment in the elderly and Alzheimer's dementia, therefore, underscores age-related sensory losses, functional disconnection between strategic brain regions in conjunction with hypoxemia and hypometabolism. On the basis of available data, it is emphasized that (A) decreases in thalamocortical function decreases cholinergic activity and cerebral blood flow, while nocturnally, (B) repeated hypoxic events affect respiratory cholinergic mechanism and respiratory regulation. Consequently, the hypotrophy/atrophy of nucleus solitarius and nucleus ambiguus in pontomedullary junction affect hypoglossal nucleus, genioglossus function, upper airway patency, hypoxia, and cerebral oxygenation. These alterations may cause amyloid-β deposition extracellularly, and neurofibrillary cytopathology in cholinergic and other neurons intracellularly. Show more

Keywords: Acetylcholine, dementia, hypoxemia, pharyngeal collapse, senescence, sensory, sleep apnea, solitarius/ambiguus

DOI: 10.3233/JAD-2010-1374

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 355-367, 2010

Authors: Butterfield, D. Allan | Hardas, Sarita S. | Lange, Miranda L. Bader

Article Type: Review Article

Abstract: Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-β protein precursor (AβPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer's disease (AD) brain …due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) of GAPDH in AD-related apoptotic cell death is emphasized. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, apoptosis, glyceraldehyde-3-phosphate dehydrogenase, hypometabolism, oxidative stress

DOI: 10.3233/JAD-2010-1375

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 369-393, 2010

Authors: Lopez-Toledano, Miguel A. | Ali Faghihi, Mohammad | Patel, Nikunj S. | Wahlestedt, Claes

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short-term memory loss. The deposition of amyloid-β (Aβ) 1-42 into senile plaques is an established feature of AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere consequence of the events leading to AD. Nevertheless, Aβ toxicity has been probed in vitro and in vivo and increased production or decreased clearance of Aβ peptides are reported to play a major role in the development of AD. Treatment of neural stem cells with Aβ in vitro induces neuronal differentiation. …Increased neurogenesis has been also described in AD patients as well as in amyloid-β protein precursor (AβPP) transgenic mice. Adult neurogenesis is greatly enhanced in young AβPP transgenic mice, before other AD-liked pathologies, and reduced in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Aβ-induced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker. Show more

Keywords: Adult neurogenesis, Alzheimer's disease, amyloid-β peptide, biomarkers, neural stem cells

DOI: 10.3233/JAD-2010-1388

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 395-408, 2010

Authors: Hardy, John | Gwinn, Katrina

Article Type: Research Article

Abstract: Despite progress in human gene discovery, we believe that regulations regarding subject protections have not fully kept pace. We believe that weaknesses in the current regulatory system include variations in the understanding of genetic principles and in the application of regulations. We discuss what our thoughts regarding steps needed to create an environment where information is gathered from all parties involved, including via research into many of the remaining questions, in order to ensure that research participant protection is adequate, appropriate and is an evolving process which will allow it to keep pace with the rapid advances in human genetics.

DOI: 10.3233/JAD-2010-1416

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 409-413, 2010

Authors: Whitehouse, Peter J. | George, Daniel

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-091424

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 415-416, 2010

Authors: Shibata, Nobuto | Kuerban, Bolati | Komatsu, Miwa | Ohnuma, Tohru | Baba, Hajime | Arai, Heii

Article Type: Short Communication

Abstract: A recent paper reported that a variant (rs2986017) of the calcium homeostasis modulator 1 (CALHM1) gene affects risk for late-onset Alzheimer's disease (AD). This study aims to investigate whether single nucleotide polymorphisms (SNPs) of the CALHM1 gene are associated with AD. SNPs in the genes of two other CALHM subtypes, CALHM2 and CALHM3, were also studied. Our study failed to detect any association between the SNPs of the three genes and AD. Although rs729211 showed marginal association in the APOE4 negative group, the linkage disequilibrium analysis results suggest this to be a false positive.

Keywords: Alzheimer's disease, apolipoprotein E, CALHM, polymorphism

DOI: 10.3233/JAD-2010-1380

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 417-421, 2010

Authors: Froud, Kristina E. | Wardhaugh, Tina | Banks, Duncan | Saffrey, M. Jill | Stewart, Michael G.

Article Type: Short Communication

Abstract: Colostrinin™ (CLN), a complex mixture of proline-rich polypeptides derived from colostrums, can alleviate cognitive decline in early Alzheimer's disease patients. The molecular basis of the action of CLN has been studied in vitro using human neuroblastoma cell lines. The aim of the present study was to use quantitative immunocytochemistry and immunoblotting to investigate the ability of CLN to relieve amyloid-β (Aβ)-induced cytotoxicity in rat primary hippocampal neuronal cells. Our data confirm that CLN alleviates the effect of Aβ-induced cytotoxicity and causes a significant reduction in the elevated levels of the antioxidant enzyme SOD1.

Keywords: Alzheimer's disease, amyloid-β, colostrinin, hippocampus, oxidative stress, superoxide dismutase

DOI: 10.3233/JAD-2010-1382

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 423-426, 2010

Authors: Hara, Hideo | Kataoka, Seiko | Anan, Mayumi | Ueda, Akihiro | Mutoh, Tatsuro | Tabira, Takeshi

Article Type: Research Article

Abstract: Innate immunity, especially that involving macrophage function, reportedly diminishes with advancing age and in patients with Alzheimer's disease (AD). In this study, we tried to elicit the non-specific activation of peripheral macrophages by oral administration of the herbal medicine Juzen-taiho-to (JTT), to assess its effect as a possible treatment for AD patients. Amyloid-β protein precursor transgenic mice were used as a model of AD to clarify the effect of JTT. Activated macrophages derived from bone marrow cross the blood-brain barrier, and then develop into microglia, which phagocytose aggregated amyloid-β (Aβ) in senile plaques. Here we show that orally administered JTT …increased the number of CD11b-positive ramified microglia in the mouse brain. The immunohistochemical examination of brain sections stained with polyclonal anti-Aβ antibody showed reduced Aβ burden, and Aβ levels were also decreased in the insoluble fractions of brain homogenates, as determined by ELISA. Thus, the activation of peripheral macrophages by JTT might be a potential new therapeutic strategy for AD. Show more

Keywords: Alzheimer's disease, herbal medicine, Juzen-taiho-to, macrophage, microglia

DOI: 10.3233/JAD-2010-1381

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 427-439, 2010

Authors: Combs, Colin K.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-090896

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 441-443, 2010

Authors: Verwey, Nicolaas A. | Kester, Maartje I. | van der Flier, Wiesje M. | Veerhuis, Robert | Berkhof, Hans | Twaalfhoven, Harry | Blankenstein, Marinus A. | Scheltens and, Philip | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: To determine the additional value of cerebrospinal fluid (CSF) amyloid-β1-40 (Aβ40 ) next to amyloid-β1-42 (β42 ), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Aβ40 , Aβ42 , pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. …Logistic regression showed that Aβ42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Aβ42 , Tau, and Aβ40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Aβ42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau (cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step, Aβ40 (cut-off 10 ng/ml) was used to differentiate controls (PPV 68%). Applying CSF Aβ40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Aβ42 and Tau were used. CSF Aβ40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Aβ40 in differential diagnosis between FTLD, AD, and control subjects. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, cerebrospinal fluid, ELISA, frontotemporal lobar degeneration

DOI: 10.3233/JAD-2010-1392

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 445-452, 2010