Molecular Pathogenesis of Progression of Cerebral toxocariasis into Alzheimer’s-Like Disease Affected by Dysfunctional Regulation from Impaired UPS and ALS That Lead to Aberrant Βeta-Amyloid Generation and Metabolism in Brain

Project: A - Government Institutionb - Ministry of Science and Technology

Description

Cerebral toxocariasis (CT) due to cerebral invasion by Toxocara canis, which is zoonotic parasite, represents the complicated consequences in the brain. Applicant has completed and submitted the 2nd-revised version of review paper entitled “Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?” which was invited by chief-in-editor of Clinical Microbiology Reviews (IF = 16.0, 2/119, Microbiology, 2013), indicating a total of 25 clinical CT cases have been found by searching the data from PubMed from 1985-2014. Of which, one German woman with CT whose age was 65 years old present with cognitive deficit and dementia, however, the neurodegenerative condition got greatly improved after treatment with Albendazole (Richaratz & Buchkremer, 2002). Except clear knowledge of Albendazole in killing T. canis larvae in the brain through many experimental studies, it remains unknown the possible mechanisms regarding the improvements of neurodegenerative conditions which is postulated to be related to the possibly lessened inflammatory cytokine production and decreased BACE1/γ-secretase activity thus resulting in the restored function of ubiquitin-proteasome system (UPS) or autophagy-lysosome system (ALS) in degradation of neurotoxic proteins e.g., β-amyloid. In addition, it is also unclear to the possible roles of astrocytes and microglial cells involved the development of CT into Alzheimer’s disease (AD). A preliminary data in a past 3-year NSC project (NSC96-2628-B-038-004-MY3) conducted by applicant found that IFN-γ increased significantly over time and at 20 weeks post infection TNF-α also increased concomitantly, indicating inflammatory response emerged and additionally, enhanced expression of BACE-1 and resultant AβPP-C99/Aβ42 as well as neurodegeneration associated proteins (NDAPs) e.g., TGF-β1 was also observed in T. canis-infected mice brain. Meanwhile, UPS impairment was also found from the beginning period thus prompting to the postulation that the malfunction in degradation of the toxic proteins. In vitro studies found that excretory-secretory antigens derived from T. canis larvae may trigger astyrocyte to undergo apoptosis and also stimulate these cells to release NDAPs, TGF-β1. These data support to constitute a hypothesis that TcES from the brain invading T. canis larvae may stimulate astrocyte or microglial cells to release pro-inflammatory cytokines and abnormal expression of NDAPs, BACE-1 and γ-secretase as well can result in overproduction of AβPP-C99 and Aβ42 accumulation to form Aβ plaque that simultaneously work together to impair the degradation function of UPS and ALS thus leading to the development of CT to AD. We intend to spend 3 years to examine these hypotheses: 1st year: Examine whether neurodegeneration associated cognitive deficit and dementia can occur to the brain invaded by T. canis larvae which was resulted from the abnormal pro-inflammatory cytokines, BACE-1 /γ-secretase, AβPP-C99/Aβ42, NDAPs expression as well as impaired degradation function of UPS and ALS thus finally leading to development of CT to AD.; 2nd year: Examine whether neurodegenerative condition can get improved in the brain invaded by T. canis larvae that was due to lessened pro-inflammatory cytokines, BACE-1 /γ-secretase, AβPP-C99/Aβ42 and NDAPs expression as well as restored functions of UPS and ALS after proper treatment with Albendazole.; 3rd year: Prior to co-culture with TcES and astrocyte or microglial cells, those glial cells were treated with BACE-1, proteasome 20S, or mTOR inhibitor individually or combined. Thereafter, pro-inflammatory cytokines, BACE-1/γ-secretase, AβPP-C99/Aβ42 and NDAPs expression as well as functions of UPS and ALS will be assessed to provide further insights to the possible roles of astrocyte or microglial cells involved in development of CT to AD.
StatusFinished
Effective start/end date8/1/157/31/16

Keywords

  • Cerebral toxocariasis
  • β/γ-Secretase
  • UPS
  • ALS
  • Alzheimer’s disease