Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin
Authors: Akerman, S. Can | Hossain, Shireen | Shobo, Adeola | Zhong, Yifei | Jourdain, Roland | Hancock, Mark A. | George, Kelly | Breton, Lionel | Multhaup, Gerhard
Article Type: Research Article
Abstract: There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40 , Aβ42 …, Aβ34 ), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson’s disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway. Show more
Keywords: Aging, α-synuclein, amyloid-β, human skin, neurodegenerative proteins, tau
DOI: 10.3233/JAD-181191
Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 463-478, 2019
Alzheimer Amyloid Peptide Aβ 42 Regulates Gene Expression of Transcription and Growth Factors
Authors: Barucker, Christian | Sommer, Anette | Beckmann, Georg | Eravci, Murat | Harmeier, Anja | Schipke, Carola G. | Brockschnieder, Damian | Dyrks, Thomas | Althoff, Veit | Fraser, Paul E. | Hazrati, Lili-Naz | George-Hyslop, Peter St | Breitner, John C.S. | Peters, Oliver | Multhaup, Gerhard
Article Type: Research Article
Abstract: The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray …study showed that Aβ42 , at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers. Show more
Keywords: Alzheimer's disease, amyloid-β, CSF proteomics, gene regulation, ID1-3, IGFBP, immunohistochemistry, LMO4, transcription factors
DOI: 10.3233/JAD-141902
Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 613-624, 2015
Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations
Authors: Chatterjee, Pratishtha | Fagan, Anne M. | Xiong, Chengjie | McKay, Matthew | Bhatnagar, Atul | Wu, Yunqi | Singh, Abhay K. | Taddei, Kevin | Martins, Ian | Gardener, Samantha L. | Molloy, Mark P. | Multhaup, Gerhard | Masters, Colin L. | Schofield, Peter R. | Benzinger, Tammie L.S. | Morris, John C. | Bateman, Randall J. | Greenberg, Steven M. | Wermer, Marieke J.H. | van Buchem, Mark A. | Sohrabi, Hamid R. | Martins, Ralph N. | Dominantly Inherited Alzheimer Network
Article Type: Research Article
Abstract: Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared …between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε 4 (p < 0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia. Show more
Keywords: Blood biomarkers, cerebral amyloid angiopathy, early diagnosis, hereditary cerebral hemorrhage with amyloidosis - dutch type, intracerebral hemorrhage, metabolomics, vascular dementia
DOI: 10.3233/JAD-201267
Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 895-903, 2021