Journal of Alzheimer's Disease - Volume 33, issue 2

Authors: Zhang, Ling | Sheng, Shuli | Qin, Chuan

Article Type: Review Article

Abstract: The expression of histone deacetylase 6 (HDAC6)—a versatile enzyme with a known role in epigenetics—increases significantly in the hippocampus and other relevant brain regions in both patients with Alzheimer's disease (AD) and animal models of AD. However, when and how HDAC6 expression increases during the course of AD progression remains unclear. Whether HDAC6 overexpression is an underlying cause of AD or a condition resulting from AD is controversial. Mounting evidence suggests that increased HDAC6 expression contributes to AD-associated neurodegeneration, although beneficial effects have also been identified. This review article addresses recent research on HDAC6 structure and function, and highlights the …potential detrimental and protective roles of HDAC6 overexpression in AD. We hope to shed light on whether HDAC6 overexpression is associated with AD etiopathogenesis or whether it rescues AD-associated neurodegeneration compensatorily. Furthermore, we discuss new evidence showing that HDAC6 may be a therapeutic target for AD. Show more

Keywords: Alzheimer's disease, autophagy, deacetylation, histone deacetylase 6 (HDAC6), neurodegeneration

DOI: 10.3233/JAD-2012-120727

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 283-295, 2013

Authors: Fernández, Patricia L. | Britton, Gabrielle B. | Rao, K.S.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) exerts a profound burden on public health worldwide. AD etiology is unknown, and research to understand its underlying pathology has produced agents for the management of symptoms, but not a cure for the disease. Most AD drugs were developed in response to research implicating fibrillar amyloid-β (Aβ) in AD neuropathology but result in only modest short-term improvements in cognitive function, so there is agreement that additional targets need to be investigated. Evidence has implicated the immune system in AD and immunotherapy as a potential approach to AD treatment. Accumulation of microglia and astrocytes has been observed around …Aβ deposits and several reports implicate inflammatory mediators in AD pathology. Importantly, Aβ deposition has been found in the brains of AD patients and in aged people without dementia, but signs of neuroinflammation are found only in AD patients and not in normal aged individuals. Animal models suggest a complex role for immunomodulators in AD, namely, these mechanisms are likely to promote the same pathogenic processes that gave rise to them. To date, clinical trials with anti-inflammatories and other immunoregulators have not been successful, but available data strongly favor immunomodulation as a promising disease intervention strategy. This article reviews data that implicate various immunomodulators in AD and considers their potential application in the development of novel AD therapeutics. Currently, a deeper understanding of nervous-immune interactions during normal aging and at all stages of AD is needed. Continued research in AD inflammatory and immunoregulatory processes will increase both our understanding of disease mechanisms and the likelihood of discovering new therapeutic targets for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, immunotargets, inflammation, microglia

DOI: 10.3233/JAD-2012-121222

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 297-312, 2013

Authors: Friedland, Robert P. | Nandi, Shivani

Article Type: Editorial

Abstract: Many studies have documented the role of risk and protective factors for late life dementing illnesses, particularly Alzheimer's disease. A “Systematic Review” from the US Agency for Healthcare Research and Quality and the National Institute on Aging concluded that because the overall quality of evidence was low, recommendations for public health could not be made. In order to gain evidence for the efficacy of lifestyle interventions, we propose a “Modest Proposal” to study 10,000 subjects over 40 years randomly assigned to groups of low or high saturated fat in the diet, head injury, and high or low levels of mental …activity, physical activity, or inactivity as well as smoking or non-smoking. This proposed study cannot be accomplished. The “Modest Proposal” illustrates that the absence of definitive evidence should not restrict physicians from making reasonable recommendations based on the evidence that is available. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, prevention, risk factors

DOI: 10.3233/JAD-2012-121459

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 313-315, 2013

Authors: Berry, Alessandra | Vacirca, Davide | Capoccia, Sara | Bellisario, Veronica | Malorni, Walter | Ortona, Elena | Cirulli, Francesca

Article Type: Short Communication

Abstract: Previous studies have suggested a pathogenetic role of autoantibodies (Abs) against ATP synthase (ATPs) in patients with Alzheimer's disease (AD). Using a mouse model, we found that intracerebroventricular administration of anti-ATPs-Abs, purified from AD patients, leads to poor cognitive performance and pronounced cell damage in the hippocampus, a brain region specifically involved in learning and memory processes, which is severely affected in AD. Our results are suggestive of a role of anti-ATPs-Abs in the onset and progression of AD and also provide a fruitful model for the study of memory disturbances in neurodegenerative diseases.

Keywords: Alzheimer's disease, apoptosis, ATP synthase, autoantibodies, maze learning, memory, mice

DOI: 10.3233/JAD-2012-121312

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 317-321, 2013

Authors: Satizabal, Claudia L. | Zhu, Yi-Cheng | Dufouil, Carole | Tzourio, Christophe

Article Type: Short Communication

Abstract: Recent studies suggest dilated Virchow-Robin Spaces (dVRS) could be a manifestation of cerebral small-vessel disease, but little is known about their risk factors. As inflammation has been associated with other brain MRI findings, we investigated whether interleukin-6 and C-reactive protein were associated with the severity of dVRS in the eldery. dVRS were assessed in basal ganglia and white matter and rated on a severity scale. We found that elevated interleukin-6 levels were associated with higher severity of dVRS in basal ganglia, suggesting that inflammation might be associated with the burden of dVRS in the elderly.

Keywords: Aged, cerebral small vessel diseases, dilated Virchow-Robin spaces, inflammation, magnetic resonance imaging

DOI: 10.3233/JAD-2012-120874

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 323-328, 2013

Authors: Yang, Yan | Ma, Delin | Wang, Yuping | Jiang, Teng | Hu, Shuhong | Zhang, Muxun | Yu, Xuefeng | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Recent studies have demonstrated that insulin plays important roles in the brain, including regulation of glucose metabolism and modulation of learning and memory. We have found dysregulation of brain insulin signaling in both Alzheimer's disease (AD) and type 2 diabetes (T2D), which correlates to hyperphosphorylation of tau, a key abnormal tau modification leading to neurofibrillary tangles. Here, we investigated tau phosphorylation and the two key components of the insulin signaling pathway, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β), in a rat model of T2D produced by a high protein, high glucose, and high fat diet followed by intraperitoneal …injection of streptozocin. We found tau hyperphosphorylation, decreased AKT activation, and GSK-3β over-activation in T2D rat brains. Intranasal insulin treatment for four weeks normalized AKT and GSK-3β, as well as reduced tau hyperphosphorylation in T2D rat brains, whereas four-week treatments with subcutaneous insulin had minimal effects on brain GSK-3β and tau phosphorylation. These results suggest decreased brain insulin signaling and tau hyperphosphorylation in the rat model of T2D and demonstrate the efficacy of intranasal insulin treatment to reverse these brain abnormalities. Our findings provide further mechanism by which T2D increases the risk for AD and also support the potential use of intranasal insulin for the treatment of AD. Show more

Keywords: Alzheimer's disease, AKT, GSK-3β, insulin, intranasal, tau hyperphosphorylation, type 2 diabetes

DOI: 10.3233/JAD-2012-121294

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 329-338, 2013

Authors: Opattova, Alena | Filipcik, Peter | Cente, Martin | Novak, Michal

Article Type: Research Article

Abstract: Misfolded, N- and C-terminally truncated tau protein is the primary constituent of neurofibrillary tangles in brains of patients afflicted with Alzheimer's disease (AD). Intracellular accumulation of misfolded and truncated tau leads to generation of cytotoxic intermediates; transgenic expression of truncated tau leads to neurological deficits, neurofibrillary degeneration, and premature death of animals. Since no cure for AD or other tauopathies is available yet, we tested the possibility for prevention of pathogenic events elicited by tau, via inhibition of its intracellular accumulation. Using a cell model conditionally expressing truncated and misfolding-prone tau protein, we showed that pathogenic forms of tau are …degraded via the proteasome. We have also observed that chymotrypsin-like activity of the proteasome was significantly suppressed (a decrease of ∼29.12% in comparison to control cells; p < 0.001) as a consequence of truncated tau expression. Interestingly, the activity of the proteasome was enhanced by geldanamycin, a natural inhibitor of Hsp90. This activation resulted in accelerated degradation of misfolded tau. We suggest that non-toxic inhibitors of Hsp90, especially those which can activate the proteasome, are good candidates for the development of molecules that efficiently counteract the damaging effects of pathologically misfolded proteins. Show more

Keywords: Cellular model, geldanamycin, proteasome, protein tau

DOI: 10.3233/JAD-2012-121072

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 339-348, 2013

Authors: Natalia Silva, Patrícia | Furuya, Tatiane Katsue | Sampaio Braga, Ianna | Rasmussen, Lucas Trevizani | de Labio, Roger Willian | Bertolucci, Paulo Henrique | Chen, Elizabeth Suchi | Turecki, Gustavo | Mechawar, Naguib | Payão, Spencer Luiz | Mill, Jonathan | Cardoso Smith, Marília

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a highly prevalent type of dementia in the elderly population. AD is a complex neurodegenerative disorder. Thus, epigenetic mechanisms that regulate gene expression might have an important role in AD. CNP (2′,3′-Cyclic Nucleotide 3′ Phosphodiesterase) gene encodes a protein used as an index of myelin alterations. DPYSL2 (Dihydropyrimidinase-like 2) is described as acting in structural and regulatory processes in the central nervous system, such as neural differentiation, neurotransmitter release, and stabilization of microtubules. In this study, we evaluated gene expression and epigenetic regulation of CNP and DPYSL2 genes in three postmortem brain regions (entorhinal and auditory …cortices and hippocampus) of AD patients and healthy elderly controls. mRNA quantification was performed using qRT-PCR, and promoter DNA methylation patterns were determined by mass spectrometry using the Sequenom EpiTYPER platform. We observed CNP mRNA downregulation in entorhinal and auditory cortex in relation to the same regions of the control group. CNP alterations in the brain might suggest impairment in myelination leading to a synaptic and cognition loss. No AD-associated differences in CNP and DPYSL2 promoter DNA methylation were observed, suggesting that other mechanisms may be involved in mediating the observed CNP gene expression. Show more

Keywords: CNP, DPYSL2, epigenetics, gene expression, mRNA

DOI: 10.3233/JAD-2012-121192

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 349-355, 2013

Authors: Capsoni, Simona | Carlo, Anne-Sophie | Vignone, Domenico | Amato, Gianluca | Criscuolo, Chiara | Willnow, Thomas E. | Cattaneo, Antonino

Article Type: Research Article

Abstract: Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve …growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD. Show more

Keywords: Amyloid, anti-NGF, cholinergic deficit, memory impairment, LR11, SorLA, tau, TrkA

DOI: 10.3233/JAD-2012-121399

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 357-371, 2013

Authors: O'Bryant, Sid E. | Johnson, Leigh | Balldin, Valerie | Edwards, Melissa | Barber, Robert | Williams, Benjamin | Devous, Michael | Cushings, Blair | Knebl, Janice | Hall, James

Article Type: Research Article

Abstract: The purpose of the study was to provide characterization of Mexican Americans who meet criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI). For the study, 1,069 participants ages 40 and above who self-identified as either non-Hispanic white (n = 633) or Mexican American (n = 436) were recruited using a community-based participatory research approach. Global cognition was assessed via the Mini-Mental State Examination (MMSE), dementia severity by the Clinical Dementia Rating Scale, and depression via the Geriatric Depression Scale 30-item version. Age, gender, education, ApoE ε4 allele frequency, and diabetic diagnoses were also analyzed. The findings showed that …Mexican Americans (normal controls, MCI, and AD) were younger, less highly educated, performed more poorly on the MMSE, endorsed more symptoms of depression, were more likely to be diagnosed with diabetes, and possessed the ApoE ε4 allele less frequently. Age was the only significant risk factor for cognitive dysfunction (AD/MCI) among Mexican Americans (OR = 1.06, 95% CI = 1.03–1.09). Age (B = 0.07, std = 0.02, p < 0.001) and ApoE ε4 presence (B = 0.9, std = 0.4, p = 0.02) were significantly related to increased disease severity. Given the rapidly growing and aging Mexican American population, there is a substantial need for research into cognitive aging, MCI, and AD among this ethnic group. The current findings hold important implications for both clinic and research settings and point to additional research needs. Show more

Keywords: Alzheimer's disease, cognition, depression, diabetes, Hispanic, Mexican American, mild cognitive impairment

DOI: 10.3233/JAD-2012-121420

Citation: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 373-379, 2013