Volume 12, Number 2, September 2007

Pages 115-127
Jennifer Horgan, Jose Javier Miguel-Hidalgo, Martha Thrasher, Garth Bissette (Communicated by Peter Whitehouse)
Longitudinal Brain Corticotropin Releasing Factor and Somatostatin in a Transgenic Mouse (TG2576) Model of Alzheimer’s disease
Abstract: Neuropeptides corticotropin releasing factor (CRF) and somatostatin (SRIF) are substantially decreased in cortical regions of Alzheimer's disease (AD) post-mortem brain tissue. The accumulation of beta amyloid (Aβ) in AD brain has been postulated to be neurotoxic. Using male Tg2576 mice transgenic over-expressing amyloid precursor protein (APP), we examined brain concentrations of CRF and SRIF at 12, 18 and 24 months. Mice were evaluated for locomotor activity and spatial memory. The APP mice had continued increased locomotor activity from 6 months of age compared to controls. Spatial memory was impaired beginning at 12 months in the APP mice relative to controls. APP mice at 24 months had a significantly higher number of amyloid plaques when compared to the 12 and 18 month time points. Brain concentrations of SRIF and CRF were significantly altered in a number of cortical and sub-cortical brain regions relative to controls, but in most regions were increased rather than decreased as in clinical AD. This data shows that although the insertion of the APP gene does cause age dependent increase in plaque load, it does not cause a change in regional neuropeptides consistent with AD, suggesting that neuropeptide changes in AD are not solely due to Aβ load.

Pages 129-142
Stephanie J. Fuller, Robert S. Tan, Ralph N. Martins
Androgens in the etiology of Alzheimer's disease in aging men and possible therapeutic interventions
Abstract: Animal experiments and cell biology studies have provided evidence that both estrogens and androgens can play a protective role against Alzheimer's disease (AD) related neurodegeneration. Males who become hypogonadal in later life often report problems with their memory. Lower than normal testosterone levels have also been detected in patients prior to the onset of AD, as well as in younger late-onset male AD patients, when compared to appropriate controls. The results of some small clinical trials suggest that testosterone can improve cognitive function in andropause. Although such improvement in cognitive function is subtle, patients on testosterone replacement therapy have reported memory improvements in both declarative and procedural domains. In contrast, there is no clinical evidence to date which suggest that the hormone dihydroepiandrosterone (DHEA) can improve cognitive function. Rises in the levels of the gonadatropins, follicle stimulating hormone (FSH) and luteinising hormone (LH), have been associated with AD, but the clinical effects of reducing their levels remain to be determined. We hypothesize that androgens, gonadotropin modulators, or perhaps selective androgen receptor modulators may be useful components of therapy aimed at preventing the onset or delaying the progression of AD in male patients.

Pages 143-149
Mustapha Bourhim, Tara Johnson, Derek Oyston, Thamarapu Srikrishnan (Communicated by Sudha Seshadri)
Thiophilic Interaction Chromatography (TIC) of Amyloid-β Protein Precursor
Abstract: Neuritic plaques, one of the diagnostic characteristics of an AD, contain extracellular deposits of amyloid-β (Aβ) derived from amyloid-β protein precursor (AβPP). The objective of this study was to extract AβPP out of HEK293 cells and to purify it. Two procedures were chosen for purification of AβPP: Thiophilic Interaction Chromatography (TIC) and molecular sieving. Using Superdex 75, Superose 12, and Fractogel gel matrices, AβPP was isolated on HPLC. The chromatograms illustrate the purification of AβPP. Our method describes a new and elegant way for the extraction and purification of AβPP from HEK293 cell lines using thiophilic interaction chromatography (TIC).

Pages 151-156
Asija Zaciragic, Orhan Lepara, Amina Valjevac, Selma Arslanagic, Almir Fajkic, Almira Hadzovic-Dzuvo, Nesina Avdagic, Azra Alajbegovic, Enra Mehmedika-Suljic, Goran Coric (Communicated by Francesco Panza)
Elevated serum C-reactive protein concentration in Bosnian patients with probable Alzheimer's disease
Abstract: Studies indicate that inflammatory mechanisms may play an important role in the pathogenesis of Alzheimer's disease (AD). C-reactive protein (CRP), marker and mediator of inflammation, has been detected in lesions typical for the affected areas of AD brain. There have been conflicting reports on serum CRP concentration in AD. Scarce data exist on association of CRP and measures of adiposity in AD patients. Thus, we investigated serum CRP concentration in fifteen overweight institutionalized patients with probable AD and fifteen age-matched control subjects. Body mass index (BMI) and waist/hip ratio (WHR) were calculated for each subject included in the study. Age, systolic and diastolic blood pressure, BMI and WHR did not differ significantly between the two groups. Serum CRP concentration was significantly higher in patients with AD compared to controls (p<0.0001). Although not significant, positive correlations between serum levels of CRP and BMI and WHR were found. Obtained results support the notion that low-grade inflammation is present in patients with AD. Absence of significant association between CRP and measures of total and central adiposity in overweight AD patients needs further investigation and explanation.

Short Communication
   Pages 157-160
   Carmen Quintana Rodríguez
   About the presence of hemosiderin in the hippocampus of Alzheimer patients

Pages 161-174
Virginia García-Marín, Pablo García-López, Miguel Freire
Cajal's contributions to the study of Alzheimer disease
Abstract: Last year 2006, we commemorated two important events in the history of Neuroscience. One hundred years ago, on November 3, Alois Alzheimer (1864-1915) presented the first case of a patient with symptoms of a disease that later would be called Alzheimer's disease. One month later, on December 10, Santiago Ramón y Cajal (1852-1934) and Camilo Golgi (1843-1926) received the Nobel Prize "in recognition of their work on the structure of the Nervous System". These facts seem not to be related, but working in the Museum Cajal we found 37 histological preparations of material from patients suffering from Alzheimer's disease, revealing that Cajal also studied this disease. This paper deals with Cajal's contribution to the study of Alzheimer's disease and it is fully illustrated by original pictures of Cajal's slides preserved in the Cajal Museum, Madrid.

Mini-Forum "Mitochondria in Alzheimer Disease" (Guest Editor: Xiongwei Zhu)

Page 175
Xiongwei Zhu
Preface: Mitochondria in Alzheimer Disease

Pages 177-184
John Xi Chen, Shi Du Yan
Amyloid β-induced mitochondrial dysfunction
Abstract: As an important molecule in the pathogenesis of Alzheimer's disease (AD), amyloid-β (Aβ) interferes with multiple aspects of mitochondrial function, including energy metabolism failure, production of reactive oxygen species (ROS) and permeability transition pore formation. Recent studies have demonstrated that Aβ progressively accumulates within mitochondrial matrix, providing a direct link to mitochondrial toxicity. Aβ-binding alcohol dehydrogenase (ABAD) is localized to the mitochondrial matrix and binds to mitochondrial Aβ. Interaction of ABAD with Aβ exaggerates Aβ-mediated mitochondrial and neuronal perturbation, leading to impaired synaptic function, and dysfunctional spatial learning/memory. Thus, blockade of ABAD/Aβ interaction may be a potential therapeutic strategy for AD.

Pages 185-193
Matthew J. Picklo, Sr., Thomas J. Montine
Mitochondrial Effects of Lipid-Derived Neurotoxins
Abstract: Mitochondria play a pivotal role in the life and death of cells and likely contribute importantly to the initiation or progression of many neurodegenerative disorders. Brain is especially vulnerable to lipid peroxidation because of its enrichment in polyunsaturated fatty acids relative to other organs. Multiple studies demonstrate the elevation of numerous lipid peroxidation products and ensuing lipid-derived carbonyls in Alzheimer’s disease. In this review, we examine the data describing the effects of lipid-derived carbonyls such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein upon the function of brain mitochondria as well as review the detoxification routes of these carbonyls.  From these data, we show that the physical-chemical properties of these carbonyls influence their effects on mitochondria and that multiple essential mitochondrial functions are altered by these endogenous reactive carbonyls. Lastly, we examine the role of mitochondrial aldehyde detoxification pathways and their potential role in the development of AD.

Pages 195-206
Paula I. Moreira, Peggy L.R. Harris, Xiongwei Zhu, Maria S. Santos, Catarina R. Oliveira, Mark A. Smith, George Perry (Handling Editor: Dengshun Wang)
Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts
Abstract: In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, Nε-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1mM) and/or N-acetyl cysteine (100μM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be effected in control fibroblasts using N-methylprotoporphyrin to inhibit cytochrome oxidase assembly including that the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N-methylprotoporphyrine were reversed or attenuated by both lipoic acid and N-acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N-acetyl cysteine supplementation may be promising.

Pages 207-208
Book Review: Aging Nation: The Economics and Politics of Growing Older in America, by James Schulz and Robert Binstock, Praeger Publishers, Westport, CT, 2006, 283 pp. Reviewed by Gene D. Cohen.

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