Journal of Alzheimer's Disease - Volume 18, issue 2

Authors: Wang, Pei-Ning | Lee, Hsin-Chen | Wang, Chun-Hui | Ping, Yueh-Hsin | Liu, Tsung-Yun | Chi, Chin-Wen | Lin, Ker-Nen | Liu, Hsu-Chih

Article Type: Research Article

Abstract: There is increasing evidence of oxidative stress in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Because mitochondrial DNA (mtDNA) is susceptible to oxidative damage, somatic mtDNA mutations may be induced by oxidative stress. Most of the studies examining mitochondrial mutations have been performed on postmortem brain tissues of AD patients. This study examined peripheral blood samples of AD and MCI patients to determine if peripheral mtDNA mutations are associated with these two conditions. A total of 236 subjects, including 71 AD patients, 84 amnestic MCI patients, 41 cognitively normal aging controls, and 40 young controls, were recruited. …There was heteroplasmy of the mtDNA D310 polycytosine repeat region in 37 of 71 (52.1%) AD patients and this was significantly more frequent than in MCI patients (31.0%), normal aging (31.7%), and young controls (27.5%). However, subjects with amnestic MCI did not have a significantly higher rate of heteroplasmy in D310 than cognitively normal elderly subjects. The heteroplasmic alterations of D310 were more frequently in subjects with a larger number of polycytosine repetitions. Insertion of cytosine was the most common mutation type. The results suggest that mutations of mtDNA 310 region are frequently present in the peripheral blood of AD patients. Further prospective investigations to determine if MCI subjects with D310 mutations develop AD is warranted. Show more

Keywords: Alzheimer's disease, D310, mild cognitive impairment, mitochondrial DNA, oxidative damage

DOI: 10.3233/JAD-2009-1156

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 345-353, 2009

Authors: McCaffrey, Pat

Article Type: Research Article

DOI: 10.3233/JAD-2009-1175

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 355-363, 2009

Authors: LaManna, Joseph C.

Article Type: Book Review

DOI: 10.3233/JAD-2009-1174

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 365-366, 2009

Authors: Bissette, Garth

Article Type: Editorial

DOI: 10.3233/JAD-2009-1173

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 369-370, 2009

Authors: Bissette, Garth

Article Type: Research Article

Abstract: This review explores the data indicating that the initial production of amyloid-β precursor protein and phosphorylated tau are associated with physiological mechanisms for repair or protection of neurons exposed to significant disturbances in homeostasis. Stimuli as diverse as head injury, inhaled anesthetic agents, stimulant drugs, and both physiological (restraint) and psychological stress (social isolation) have been shown to increase brain expression of amyloid-β and hyperphosphorylated tau without accompanying neurodegeneration. This review aims to encompass these responses as indicators of normal physiological processes that, in the case of Alzheimer's disease, are either unable to successfully repair or protect vulnerable neuronal populations …from eventual neurodegeneration, but that are necessary components of an integrated nervous system that would be more susceptible to pathology if such processes were blocked in an attempt to minimize or prevent future damage. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, corticotropin releasing factor, hypothalamic-pituitary-adrenal axis, phosphorylated tau, urocortin

DOI: 10.3233/JAD-2009-1171

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 371-380, 2009

Authors: Koudinov, Alexei | Kezlya, Elena | Koudinova, Natalia | Berezov, Temirbolat

Article Type: Research Article

Abstract: In this review, we propose that the neurodegenerative changes in the neurochemistry of amyloid-β (Aβ) aggregation, tau phosphorylation, cytoskeleton rearrangement, oxidative stress, and lipid peroxidation in Alzheimer's disease (AD), and a number of other neurodegenerative diseases, are secondary pathological features. In fact, we believe that these phenomena represent natural compensatory mechanisms for impaired primary neurodegeneration, membrane dynamic deterioration, and/or associated failures of neurotransmission, synaptic function, and neuroplasticity. Physiologically, Aβ, lipid peroxidation, and tau protein may function to sense changes in activity-dependent membrane properties and therefore biochemically modulate membrane lipid homeostasis for more efficient synaptic action. As such, the previously proposed …therapeutic tackling of amyloid, tau, oxidative stress, and other brain disease markers may have no ability to cure AD or other devastating central nervous system pathologies and peripheral nervous system diseases. This unfortunate realization provides a wake-up call to the neuroscience community, demanding open-minded approach. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, apolipoprotein E, cholesterol, Down's syndrome, high density lipoprotein, hippocampus, inclusion-body myositis, lipid peroxidation, lipoproteins, low density lipoprotein, markers, neuromuscular junctions, Niemann Pick's disease, phospholipids, synaptic plasticity, tau

DOI: 10.3233/JAD-2009-1202

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 381-400, 2009

Authors: Hiltunen, Mikko | van Groen, Thomas | Jolkkonen, Jukka

Article Type: Research Article

Abstract: Amyloid-β (Aβ) has remained a central feature in research into Alzheimer's disease (AD). Yet the function of the amyloid-β protein precursor (AβPP) and its processing products in the central nervous system is controversial. This review examines experimental literature from cell cultures to transgenic AD and brain injury models with a special emphasis on the functional role of AβPP and AβPP-derived peptides. AβPP knock-out mice exhibit severe metabolic abnormalities and behavioral deficits, indicating an important physiological function of AβPP. Also, an increasing body of evidence suggests that while Aβ is undoubtedly linked to neurodegeneration, the soluble amino-terminal fragment of AβPP (sAβPPα) …has neuroprotective, neurotrophic, and cell adhesive functions. Moderate overexpression of human AβPP in rodents does not produce apparent Aβ pathology and has no significant effect on cognitive or sensorimotor behavior and, surprisingly, may even provide histological neuroprotection against focal cerebral ischemia. In contrast, phenotypes with more severe Aβ pathology show impaired cognitive performance, increased vulnerability to brain ischemia and trauma, and less favorable functional outcome even before Aβ deposition. A delicate balance in AβPP processing seems to determine its functional consequences. Thus, it is tempting to speculate that promotion of α-secretase-mediated cleavage of AβPP, which leads to increased sAβPPα production, provides a novel therapeutic strategy in the treatment of AD and brain injury. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, brain trauma, cerebral ischemia, function, mice, rat

DOI: 10.3233/JAD-2009-1154

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 401-412, 2009

Authors: Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

Abstract: Research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an ongoing development of disease-modifying treatments. These new drug candidates are targeted on inhibiting amyloid-β (Aβ) production and aggregation or tau aggregation. If these drugs prove to be efficient, diagnostic tools enabling early diagnosis of AD will be of great value. Also in drug development, it is important to co-develop biomarkers to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). …The core candidate CSF biomarkers Aβ42 , total tau (T-tau), and phosphorylated tau (P-tau) have been shown to have a high diagnostic performance to identify AD also in the early phase of the disease. This paper reviews recent research advances on these CSF biomarkers for use in clinical diagnosis and in clinical trials in AD. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, diagnosis

DOI: 10.3233/JAD-2009-1177

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 413-417, 2009

Authors: Menon, Parekkat M. | Vonsattel, Jean Paul | Jolles, Paul R.

Article Type: Research Article

Abstract: Over the past several decades, there has been extensive research devoted toward determining the cause of Alzheimer's disease. Numerous biochemical, histological, and imaging investigations have elegantly characterized the neuropathologic and functional changes associated with AD. Proponents of one theory or another can find supporting data among the myriad of studies in the literature. This paper attempts to summarize some of the major conclusions and controversies in imaging literature (especially, magnetic resonance imaging and nuclear medicine) in relation to pathogenesis theories of Alzheimer's disease. In spite of considerable progress, the primary cause of Alzheimer's disease remains elusive.

Keywords: Amyloid-β, atrophy, MRI, neurodegeneration, PET, tau, vascular

DOI: 10.3233/JAD-2009-1166

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 419-427, 2009

Authors: Kadish, Inga | van Groen, Thomas

Article Type: Research Article

Abstract: We have studied entorhinal cortex lesion-induced sprouting in the hippocampus in young, adult, and aged control and transgenic Alzheimer's disease model mice. The entorhinal cortex was unilaterally, partially lesioned, and four weeks later the subsequent axonal sprouting in dentate gyrus was analyzed. Our data demonstrate that young and adult, control and amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) mice display a significantly increased density of staining for synaptophysin in dentate gyrus, indicative of axonal sprouting. However, whereas young and adult mice demonstrate sprouting, aged mice (control and AβPP/PS1) do not show a significant upregulation of synaptophysin staining following the lesions. In …contrast, aged mice overexpressing PS1 show an increased regenerative response compared to age-matched control mice and mice overexpressing AβPP which do not show sprouting. Further, the data demonstrate that a significant Aβ load in the dentate gyrus does not prevent axonal sprouting. Lastly, only aged mice show significant shrinkage of the molecular layer of dentate gyrus following entorhinal cortex lesions. Further, adult ovariectomized females (control and AβPP/PS1) are significantly reduced in their plasticity following lesions. Taken together, the data indicate that amyloid-β deposits do not negatively impact plasticity in the brain and that overexpression of AβPP is not beneficial, but that normal estrogen levels are beneficial for plasticity. Show more

Keywords: Entorhinal cortex, hippocampus, mouse, plasticity, sex and gene differences, sprouting

DOI: 10.3233/JAD-2009-1157

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 429-445, 2009

Authors: Castellani, Rudy J. | Lee, Hyoung-gon | Siedlak, Sandra L. | Nunomura, Akihiko | Hayashi, Takaaki | Nakamura, Masao | Zhu, Xiongwei | Perry, George | Smith, Mark A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-β as the major pathogenic mechanism with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with …the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on “proteinopathies” and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor (AβPP) processing, antioxidant, cellular toxicity, oligomers, oxidative stress

DOI: 10.3233/JAD-2009-1151

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 447-452, 2009

Authors: Rissman, Robert A.

Article Type: Research Article

Abstract: Abnormally phosphorylated tau protein is a key component of the pathology seen in neurodegenerative tauopathies, such as Alzheimer's disease (AD). Despite its association with disease, tau phosphorylation (tau-P) also plays an important role in neuroplasticity, such as dendritic/synaptic remodeling seen in the hippocampus in response to environmental challenges, such as stress. To define the boundaries between neuroplasticity and neuropathology, studies have attempted to characterize the paradigms, stimuli, and signaling intermediates involved in stress-induced tau-P. Supporting an involvement of stress in AD are data demonstrating alterations in stress pathways and peptides in the AD brain and epidemiological data implicating stress exposure …as a risk factor for AD. In this review, the question of whether stress-induced tau-P can be used as a model for examining the relationship between functional neuroplasticity and neuronal vulnerability will be discussed. Show more

Keywords: Alzheimer's disease, corticotropin-releasing, hippocampus, hypothalamus, neurofibrillary tangles, phosphorylation, stress, tau

DOI: 10.3233/JAD-2009-1153

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 453-457, 2009

Authors: Dong, Hongxin | Csernansky, John G.

Article Type: Research Article

Abstract: Growing evidence indicates that physical and psychosocial stressors, in part acting through the hypothalamic-pituitary-adrenal (HPA) axis, may accelerate the process of Alzheimer's disease (AD). In this review, we summarize recent research related to the effects of stress and stress hormones on the various disease process elements associated with AD. Specifically, we focus on the relationships among chronic stressors, HPA axis activity, amyloid-β protein, and amyloid-β plaque deposition in mouse models of AD. The potential mechanisms by which stress and stress-related components, especially corticotrophin-releasing factor and its receptors, influence the pathogenesis of AD are discussed.

Keywords: Alzheimer's disease, amyloid-β, corticotrophin-releasing factor (CRF) and receptors (CRFRs), hypothalamic-pituitary-adrenal (HPA) axis, stress, Tg2576 mice

DOI: 10.3233/JAD-2009-1152

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 459-469, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1172B

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 471-472, 2009