Upregulated Expression of Heparanase and Heparanase 2 in the Brains of Alzheimer’s Disease

Article type: Research Article

Authors: García, Beatriz^{a; b} | Martín, Carla^{a; b} | García-Suárez, Olivia^{b; c} | Muñiz-Alonso, Bárbara^a | Ordiales, Helena^a | Fernández-Menéndez, Santiago^d | Santos-Juanes, Jorge^e | Lorente-Gea, Laura^f | Castañón, Sonia^g | Vicente-Etxenausia, Ikerne^h | Piña Batista, Kelvin Manuelⁱ | Ruiz-Díaz, Irune^j | Caballero-Martínez, María Cristina^{j; k} | Merayo-Lloves, Jesús^b | Guerra-Merino, Isabel^f | Quirós, Luis M.^{a; b} | Fernández-Vega, Iván^{b; e; f; h; *}

Affiliations: [a] Department of Functional Biology, University of Oviedo, Spain | [b] Instituto Universitario Fernández-Vega, Oviedo, Spain | [c] Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain | [d] Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain | [e] Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain | [f] Department of Pathology, Hospital Universitario de Araba-Txagorritxu, Spain | [g] Department of Biotechnology, Neiker-Tecnalia Arkaute, Vitoria-Gasteiz, Spain | [h] Biobanco Vasco para la Investigación (O+eHun), Brain Bank, Hospital Universitario Araba, Spain | [i] Department of Neurosurgery, Hospital Universitario Central de Asturias, Oviedo, Spain | [j] Department of Pathology, Hospital Universitario Donostia, Gipuzkoa, Spain | [k] Biobanco Vasco para la Investigación (O+eHun), Brain Bank Hospital Universitario Donostia, Spain

Correspondence: [*] Correspondence to: Dr. Ivan Fernandez-Vega, MD, PhD, Service of Anatomic Pathology, Hospital Universitario de Araba-Txagorritxu, C/Jose Atxotegui s/n, E-01009, Vitoria-Gasteiz, Alava, Spain. Tel.: +34 945007001; E-mail: ivan_fernandez_vega@hotmail.com.

Abstract: Background: Heparan sulfate proteoglycans (HSPGs) promote amyloid-β peptide and tau fibrillization in Alzheimer’s disease (AD) and provide resistance against proteolytic breakdown. Heparanase (HPSE) is the only enzyme that cleaves heparan sulfate (HS). Heparanase 2 (HPSE2) lacks HS-degrading activity, although it is able to interact with HS with high affinity. Objective: To analyze HPSE and HPSE2 expressions at different stages of AD. Methods: RT-PCR was used to analyze transcription levels of both heparanases at different stages of AD, and immunohistochemistry was performed to localize each one in different parts of the brain. Results: Both proteins appeared overexpressed at different stages of AD. Immunohistochemistry indicated that the presence of the heparanases was related to AD pathology, with intracellular deposits found in degenerated neurons. At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well. Conclusion: Given the involvement of HSPGs in AD pathology, there would seem to be a relationship between the regulation of heparanase expression, the features of the disease, and a possible therapeutic alternative.

Keywords: Alzheimer’s disease, amyloid, amyloid-β, glycosaminoglycan, heparan sulfate, heparanase

DOI: 10.3233/JAD-161298

Journal: Journal of Alzheimer's Disease, vol. 58, no. 1, pp. 185-192, 2017