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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: Schreiber, Stefanie | Drukarch, Benjamin | Garz, Cornelia | Niklass, Solveig | Stanaszek, Luiza | Kropf, Siegfried | Bueche, Celine | Held, Friederike | Vielhaber, Stefan | Attems, Johannes | Reymann, Klaus G. | Heinze, Hans-Jochen | Carare, Roxana O. | Wilhelmus, Micha M.M.

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer’s disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. Objective: We test the hypothesis that characteristic features of CSVD are associated with the accumulation of Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Methods: Amyloid-β protein precursor (AβPP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for BBB examination were performed …in 38 SHRSP (age 12–44 weeks) and Aβ (n = 29) and ptau (n = 17) immunocytochemistry in 20–44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12–44 weeks). Results: In 20 week-old SHRSP, cortical AβPP expression was significantly increased compared to Wistar controls but tau levels were unchanged. At ages of 20–44 weeks, SHRSP exhibited an age-dependent increase in extracellular Aβ. Ptau was observed in 26–44 week-old SHRSP. Distinct features of CSVD pathology developed from the age of 12 weeks on. Conclusion: We demonstrate that in a hypertensive rat model that displays features of CSVD from 12 weeks, there is an age-dependent extracellular deposition of Aβ observed from 20 weeks onwards, increased AβPP expression at 20 weeks and ptau accumulation from 26 weeks on. This study suggests that CSVD associated with hypertension results in an age-related failure of Aβ clearance, increase in AβPP expression, and intraneuronal tau hyperphosphorylation. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, cerebral small vessel disease, hyperphosphorylated tau, spontaneously hypertensive stroke-prone rats

DOI: 10.3233/JAD-132618

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S205-S215, 2014