Journal of Alzheimer's Disease - Volume 42, issue s3

Authors: Wilhelmus, Micha M.M. | de Jager, Mieke | Bakker, Erik N.T.P. | Drukarch, Benjamin

Article Type: Review Article

Abstract: Protein misfolding and the formation of stable insoluble protein complexes by self-interacting proteins, in particular amyloid-β and tau protein, play a central role in the pathogenesis of Alzheimer's disease (AD). Unfortunately, the underlying mechanisms that trigger the misfolding of self-interacting proteins that eventually results in formation of neurotoxic dimers, oligomers, and aggregates remain unclear. Elucidation of the driving forces of protein complex formation in AD is of crucial importance for the development of disease-modifying therapies. Tissue transglutaminase (tTG) is a calcium-dependent enzyme that induces the formation of covalent ε-(γ-glutamyl)lysine isopeptide bonds, which results in both intra- and intermolecular protein cross-links. …These tTG-catalyzed intermolecular cross-links induce stable, rigid, and insoluble protein complexes, whereas intramolecular cross-links change the conformation of proteins. Inhibition of tTG-catalyzed cross-linking counteracts the formation of protein aggregates, as observed in disease-models of other protein misfolding diseases, in particular Parkinson's and Huntington's diseases. Although data of tTG activity in AD models is limited, there is compelling evidence from both in vitro and postmortem human brain tissue of AD patients that point toward a crucial role for tTG in the pathogenesis of AD. Here, we review these data on the role of tTG in the initiation and development of protein aggregates in AD, and discuss the possibility to use inhibitors of the cross-linking activity of tTG as a new therapeutic approach for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebral amyloid angiopathy, crosslinking, neurofibrillary tangles, senile plaques, therapy, tissue transglutaminase

DOI: 10.3233/JAD-132492

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S289-S303, 2014

Authors: Bueche, Celine Zoe | Garz, Cornelia | Stanaszek, Luiza | Niklass, Solveig | Kropf, Siegfried | Bittner, Daniel | Härtig, Wolfgang | Reymann, Klaus G. | Heinze, Hans-Jochen | Carare, Roxana O. | Schreiber, Stefanie

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is accompanied by parenchymal amyloid-β (Aβ) deposition in the brain and by hypertensive nephropathy with tubulointerstitial damage. N-acetylcysteine (NAC) promotes blood-brain barrier (BBB) breakdown in SHRSP and may thus accelerate the failure of vascular and perivascular clearance of Aβ. Objective: In this study, we test the hypothesis that treatment with NAC increases the cerebral Aβ load and improves renal damage in the SHRSP model. Methods: A total of 46 SHRSP (ages 18–44 weeks) were treated daily with NAC (12 mg/kg body weight) and …74 no-treated age-matched SHRSP served as controls. The prevalence of parenchymal Aβ load, IgG positive small vessels, and small perivascular bleeds was assessed in different brain regions. Tubulointerstitial kidney damage was assessed through a) the presence of erythrocytes in peritubular capillaries and b) tubular protein cylinders. Results: SHRSP treated with NAC had an age-dependent increase of BBB breakdown (assessed by the presence of IgG positive small vessels) and small perivascular bleeds, mainly in the cortex. NAC significantly increased the Aβ plaque load in the cortex while the number of parenchymal amyloid deposits in the remaining brain areas including basal ganglia, hippocampus, thalamus, and corpus callosum were unchanged. There were no significant treatment effects on tubulointerstitial kidney damage. Conclusion: The impact of NAC on cerebral cortical plaque load increase may result from the vascular pathology of SHRSP that accompanies BBB breakdown, leading to the failure of amyloid clearance mechanisms. It remains to be seen whether in humans chronic NAC intake may increase amyloid load in the aging human brain and dementia. Show more

Keywords: Amyloid-β, cerebral small vessel disease, hypertensive nephropathy, N-acetylcysteine rats, spontaneously hypertensive stroke prone rats (SHRSP)

DOI: 10.3233/JAD-132615

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S305-S313, 2014

Authors: Giannopoulos, Sotirios | Katsanos, Aristeidis H. | Kosmidou, Maria | Tsivgoulis, Georgios

Article Type: Review Article

Abstract: The impact of statin therapy on dementia has been a hot topic of debate over the last decade and still remains highly controversial. Among all causes of dementia, vascular dementia (VaD) is the one type that is more likely to benefit from statins. To date no randomized clinical trials have been published and no systematic review has investigated a possible preventive effect of statins on the VaD subtype. In the present literature review, we tried to identify all available data on the effect of statins specifically in patients with VaD, and to further discuss this possible association. Our literature search …highlighted two cross-sectional studies, two prospective cohort studies, and one retrospective cohort study. Two of the studies found a significant positive effect of statin treatment on VaD, depicted by the lower incidence of VaD in statin users, while the others reported non-significant associations. The relatively small numbers of VaD patients and statin users, as well as the presence of confounders and biases, make the interpretation of results extremely difficult. Statins may exert a benefit in the prevention of all-type dementia and VaD, through several mechanisms except for hyperlipidemia reduction. A well-designed randomized clinical trial is the ideal study design to address the effect of statin therapy in VaD and to draw final conclusions. Show more

Keywords: Cholesterol, HMG-CoA inhibitors, lipid lowering agents, statins, vascular dementia

DOI: 10.3233/JAD-132366

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S315-S320, 2014

Authors: de Oliveira, Fabricio Ferreira | Bertolucci, Paulo Henrique Ferreira | Chen, Elizabeth Suchi | Smith, Marilia Cardoso

Article Type: Short Communication

Abstract: Controversy over benefits of angiotensin-converting enzyme inhibitors (ACEIs) for treatment of dementia due to Alzheimer's disease (AD) led to this alternative investigational approach by the employment of pharmacogenetic methods, correlating the cognitive change of patients with late-onset AD with the presence of common ACE gene promoter polymorphisms, and stratifying the sample in groups of patients who responded or not to the brain-penetrating ACEIs Captopril or Perindopril. A trend was found for treatment with brain-penetrating ACEIs to slow cognitive decline in AD patients with the haplotype rs1800764 (CC): rs4291 (TT) (p = 0.024), and also non-significantly for independent carriers of rs1800764 …or rs4291. Show more

Keywords: Alzheimer's disease, dementia, drug therapy, neurodegenerative diseases, neuropsychiatry, pharmacogenetics

DOI: 10.3233/JAD-132189

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S321-S324, 2014

Article Type: Other

DOI: 10.3233/JAD-149901

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S325-S325, 2014