Abstract
Background: The deposition of β-sheet rich amyloid in senile plaques is a pathological hallmark of Alzheimer’s disease (AD), which is thought to cause neuronal dysfunction. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated β-amyloid (Aβ) is able to induce cerebral amyloidosis thus causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption.Methods: We investigated whether cerebral transmission of Aβ was possible via oral administration of Aβ-rich brain extract in non-susceptible and susceptible host mice by immunohistochemistry, western blotting and behavior tests. Also brain extracts were supplied to AD transgenic Caenorhabditis elegans, and paralysis curve were conducted, following detection of Aβ amyloid. RNA sequencing of nematodes was applied then inhibitors for relevant dysregulated genes were used in the paralysis induction.Results: The oral treatment of AD brain extract or normal brain extract neither aggravated nor mitigated the Aβ load, glial activation or the abnormal behaviors in recipient Amyloid precursor protein/presenilin 1 (APP/PS1) mice. Whereas, a significant improvement of AD pathology was detected in worms treated with Aβ-rich or normal brain extracts, which was attributable to the heat-sensitive components of brain extracts. Transcriptome sequencing of CL4176 nematodes suggested that brain extracts could delay worm paralysis through multiple pathways, including ubiquitin mediated proteolysis and Transforming growth factor β (TGF-β) signaling pathway. Inhibitors of the ubiquitin proteasome system and the TGF-β signaling pathway significantly blocked the suppressive effects of brain extracts on worm paralysis.Conclusions: Our results suggest that systemic transmissible mechanisms of prion proteopathy may not apply to β amyloid, at least in terms of oral administration. However, brain extracts strongly ameliorated AD pathology in AD transgenic nematodes partially through TGF-β signaling pathway and ubiquitin mediated proteolysis, which indicated that some natural endogenous components in the mammalian tissues could resist Aβ toxicity.
Highlights
MATERIALS AND METHODSA number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease and the prion diseases ( called Creutzfeldt-Jakob disease (CJD)), are characterized by the aberrant aggregation of specific proteins and referred as the proteopathies (Selkoe, 2003)
Many studies have proven that intracerebral infusion of brain extract from AD patients or AD transgenic mice can induce cerebral β-amyloidosis in AD transgenic mice (Kane et al, 2000; Meyer-Luehmann et al, 2006; Hamaguchi et al, 2012; Heilbronner et al, 2013) and nonhuman primates (Ridley et al, 2006), which was reminiscent with the prion transmission
We found that brain extracts markedly delayed the onset of paralysis in worms expressing human Aβ1–42 and the protective effect of brain extracts were dose dependent, with 5% brain extracts showing better effects compared with 0.1% brain extracts (P < 0.0001 and P = 0.039 for WT and AD transgenic mouse brain extracts, respectively; Figures 1A,B)
Summary
MATERIALS AND METHODSA number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease and the prion diseases ( called Creutzfeldt-Jakob disease (CJD)), are characterized by the aberrant aggregation of specific proteins and referred as the proteopathies (Selkoe, 2003). It is well known that prion diseases can be induced by conformationally variant prion from contaminated food or iatrogenic transmission. Many studies have proven that intracerebral infusion of brain extract from AD patients or AD transgenic mice can induce cerebral β-amyloidosis in AD transgenic mice (Kane et al, 2000; Meyer-Luehmann et al, 2006; Hamaguchi et al, 2012; Heilbronner et al, 2013) and nonhuman primates (Ridley et al, 2006), which was reminiscent with the prion transmission. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated β-amyloid (Aβ) is able to induce cerebral amyloidosis causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption
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