Journal of Alzheimer's Disease - Volume 37, issue 2

Authors: Kazmerova, Zuzana | Zilka, Norbert | Cente, Martin | Neradil, Peter | Zilkova, Monika | Novak, Michal

Article Type: Review Article

Abstract: Human neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease represent unmet medical need. There is no effective cure available on the market. Several novel therapeutic approaches targeting fundamental features of these disorders have been proposed during the last two decades. Cell therapy represents one of the most promising therapeutic avenues targeting different pathological traits of these disorders. However, there are some caveats that should be taken into the consideration including ethical issues and limited utilization for routine clinical practice. It is unlikely that cell therapy constitutes the ‘magic bullet’ therapeutic approach that would meet all therapeutic needs. However, in …the future it can potentially bolster the effect of disease modifying drugs by improving the brain environment and regulation of inflammatory and neurotrophic pathways. Show more

Keywords: Alzheimer disease, cell replacement therapy, Parkinson disease, regenerative therapy, stem cells

DOI: 10.3233/JAD-130572

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 251-272, 2013

Authors: Mroczko, Barbara | Groblewska, Magdalena | Barcikowska, Maria

Article Type: Review Article

Abstract: Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer's disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to …induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-β (Aβ). It has also been shown that Aβ enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aβ-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia. Show more

Keywords: Alzheimer's disease, amyloid-β, dementia, matrix metalloproteinases, neurodegeneration, tau protein, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-130647

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 273-283, 2013

Authors: Bernardi, Livia | Gallo, Maura | Anfossi, Maria | Conidi, Maria Elena | Colao, Rosanna | Puccio, Gianfranco | Curcio, Sabrina A.M. | Frangipane, Francesca | Clodomiro, Alessandra | Mirabelli, Maria | Vasso, Franca | Smirne, Nicoletta | Di Lorenzo, Raffaele | Maletta, Raffaele | Bruni, Amalia C.

Article Type: Short Communication

Abstract: We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose-dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory …performance could be influenced by TOMM40 genotypes. Show more

Keywords: Familial Alzheimer's disease, large kindreds, onset variability, performance on memory, PSEN1 M146L mutation, TOMM40 rs10524523 genotype

DOI: 10.3233/JAD-130119

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 285-289, 2013

Authors: Sun, Lei | Tan, Meng-Shan | Hu, Nan | Yu, Jin-Tai | Tan, Lan

Article Type: Short Communication

Abstract: BIN1, as an important genetic susceptibility locus in late-onset Alzheimer's disease (AD), is overexpressed in AD brains. Our study investigated BIN1 diagnostic value by quantifying its transcription level and plasma expression from 112 AD and 200 control subjects. We observed significant increase in BIN1 mRNA and protein levels in AD patients. Receiver operating characteristic curve analysis shown the sensitivity and specificity were 73% and 75% for plasma BIN1 in identifying AD. Although this is a pilot study requiring corroboration on a larger cohort of patients, our results highlight the possible use of plasma BIN1 as a biomarker for AD diagnosis.

Keywords: Alzheimer's disease, BIN1, biomarker, ELISA, plasma, qRT-PCR

DOI: 10.3233/JAD-130392

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 291-295, 2013

Authors: Yang, Hongqian | Wittnam, Jessica L. | Zubarev, Roman A. | Bayer, Thomas A.

Article Type: Research Article

Abstract: AβpE3-42 (N-terminal truncated amyloid-β peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AβpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% …to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes. Show more

Keywords: Amyloid-β peptide, LC/MS, mass spectrometry, shotgun proteomics

DOI: 10.3233/JAD-130476

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 297-308, 2013

Authors: Huber, Bertrand R. | Meabon, James S. | Martin, Tobin J. | Mourad, Pierre D. | Bennett, Raymond | Kraemer, Brian C. | Cernak, Ibolja | Petrie, Eric C. | Emery, Michael J. | Swenson, Erik R. | Mayer, Cynthia | Mehic, Edin | Peskind, Elaine R. | Cook, David G.

Article Type: Research Article

Abstract: Mild traumatic brain injury (mTBI) is considered the ‘signature injury’ of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP …exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phospho- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes. Show more

Keywords: Blast-induced neurotrauma, brain trauma, cerebellum, mitochondrial oxidative stress, neurodegeneration, tauopathy

DOI: 10.3233/JAD-130182

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 309-323, 2013

Authors: Shiota, Satomi | Takekawa, Hidenori | Matsumoto, Shin-ei | Takeda, Kazuya | Nurwidya, Fariz | Yoshioka, Yasuko | Takahashi, Fumiyuki | Hattori, Nobutaka | Tabira, Takeshi | Mochizuki, Hideki | Takahashi, Kazuhisa

Article Type: Research Article

Abstract: Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimer's disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro. In vivo, 15 male triple transgenic AD mice were exposed to either CIH or normoxia (5% O2 and 21% O2 every 10 min, 8 h/day for 4 weeks). Amyloid-β (Aβ) profile, cognitive brain function, and brain pathology were evaluated. …In vitro, human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid-β protein precursor were exposed to either IH (8 cycles of 1% O2 for 10 min followed by 21% O2 for 20 min) or normoxia. The Aβ profile in the conditioned medium was analyzed. CIH significantly increased levels of Aβ42 but not Aβ40 in the brains of mice without the increase in hypoxia-inducible factor 1, alpha subunit (HIF-1α) expression. Furthermore, CIH significantly increased intracellular Aβ in the brain cortex. There were no significant changes in cognitive function. IH significantly increased levels of Aβ42 in the medium of SH-SY5Y cells without the increase in the HIF-1α expression. CIH directly and selectively increased levels of Aβ42 in the AD model. Our results suggest that OSA would aggravate AD. Early detection and intervention of OSA in AD may help to alleviate the progression of the disease. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, hypoxia, obstructive sleep apnea

DOI: 10.3233/JAD-130419

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 325-333, 2013

Authors: Pires, Carolina | Coelho, Miguel | Valadas, Anabela | Barroso, Cândida | Pimentel, José | Martins, Madalena | Duyckaerts, Charles | de Mendonça, Alexandre | Verdelho, Ana | Miltenberger-Miltenyi, Gabriel

Article Type: Research Article

Abstract: The clinical phenotype of frontotemporal dementia patients carrying progranulin (GRN) mutations is known to be heterogeneous. We present a patient with corticobasal syndrome and a family with progressive aphasia and behavioral features who were found to have the same p.Gln257Profs*27 mutation. These cases depict the variability of GRN mutation carriers regarding clinical presentation and age of onset. In addition to giving a detailed report of a GRN mutation, we highlight the importance of searching for the presence of GRN mutations in selected sporadic cases and suggest a broadening of GRN genetic screening to better understand the clinical spectrum of these …mutations. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, GRN protein, primary progressive nonfluent aphasia

DOI: 10.3233/JAD-130146

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 335-342, 2013

Authors: Descamps, Olivier | Spilman, Patricia | Zhang, Qiang | Libeu, Clare P. | Poksay, Karen | Gorostiza, Olivia | Campagna, Jesus | Jagodzinska, Barbara | Bredesen, Dale E. | John, Varghese

Article Type: Research Article

Abstract: A systematic approach was used to identify AβPP-selective BACE inhibitors (ASBI) and to evaluate their in vivo ability to modulate AβPP processing selectively. We identified a bioflavonoid nutritional supplement as a molecular lead that acts as an ASBI in cell models, and show that increasing brain levels of this bioflavonoid through a pro-drug approach leads to reduction of Aβ42 in an Alzheimer's disease mouse model. ASBIs represent a novel class of candidate therapeutic agents for Alzheimer's disease.

Keywords: Alzheimer's disease, AβPP, ASBI, galangin, pro-drug, rutin

DOI: 10.3233/JAD-130578

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 343-355, 2013

Authors: Handels, Ron L.H. | Xu, Weili | Rizzuto, Debora | Caracciolo, Barbara | Wang, Rui | Winblad, Bengt | Verhey, Frans R.J. | Severens, Johan L. | Fratiglioni, Laura | Joore, Manuela A. | Wimo, Anders

Article Type: Research Article

Abstract: Background: Empirical models of the natural history of Alzheimer’s disease (AD) may help to evaluate new interventions for AD. Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases. Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged ⩾75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function …was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models. Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender. Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD. Show more

Keywords: Alzheimer's disease, dementia, disease progression, economic model, mild cognitive impairment

DOI: 10.3233/JAD-130296

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 357-365, 2013