Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Abstract

Wnt signaling constitutes a fundamental cellular and molecular pathway, necessary from proper embryogenesis to function-maintenance of fully developed complex organisms. In this regard, Wnt pathway plays a crucial role in both the development of the central nervous system and in maintaining the structure and function of the neuronal circuits, and it has been suggested that its dysregulation is critical in the onset of several pathologies including cancer and neurodegenerative disorders, such as Alzheimer’s disease (AD). Due to its relevance in the maintenance of the neuronal activity and its involvement in the outbreak of devastating diseases, we explored the age-related changes in the expression of Wnt key components in the cortex and hippocampus of 7 to 72-months-old Octodon degus ( O. degus ), a Chilean long-living endemic rodent that has been proposed and used as a natural model for AD. We found a down-regulation in the expression of different Wnt ligands (Wnt3a, Wnt7a, and Wnt5a), as well as in the Wnt co-receptor LRP6. We also observed an increase in the activity of GSK-3β related to the down-regulation of Wnt activity, a fact that was confirmed by a decreased expression of Wnt target genes. Relevantly, an important increase was found in secreted endogenous Wnt inhibitors, including the secreted-frizzled-related protein 1 and 2 (SFRP-1 and SFRP-2) and Dickkopf-1 (Dkk-1), all them antagonists at the cell surface. Furthermore, treatment with Andrographolide, a labdane diterpene obtained from Andrographis paniculata , prevents Wnt signaling loss in aging degus . Taken together, these results suggest that during the aging process Wnt signaling activity decreases in the brain of O. degus .

Blood DNA Methylation Levels in the WNT5A Gene Promoter Region: A Potential Biomarker for Agitation in Subjects with Dementia

“…Based on the foregoing, appearance of agitation and the related changes in WNT5A DNA methylation could arise independently of peripheral inflammation so it will be necessary to examine the influence of neuroinflammation in future studies. Wnt signaling plays an important role in embryogenesis and is involved in the differentiation and development of the central nervous system [ 46, 47 ]. Further, Wnt signaling molecules are much expressed in the adult brain including the hippocampus and are involved in synapse maintenance and function [ 48 ] as well as in dopaminergic neuron formation and nerve regeneration [ 49 ].…”

Primary cilia and ciliary signaling pathways in aging and age-related brain disorders

“…The deficiency of SHH signaling in hypothalamus astrocytes prevents high-fat diet-induced obesity and insulin resistance, suggesting that astrocytic SHH signaling is a pivotal regulator in metabolic alterations associated with aging ( Tirou et al, 2021 ). A study in the Octodon degus demonstrated that Wnt signaling activity is decreased in the brain during aging ( Inestrosa et al, 2020 ). Notably, administration of ANDRO, an activator of the Wnt signaling, rescued the Wnt signaling loss in the brain of adult O. degus ( Inestrosa et al, 2020 ).…”

Molecular mechanisms of developmental pathways in neurological disorders: a pharmacological and therapeutic review

“…Studies have further revealed that Wnt ligands (Wnt-2b, Wnt-6 and Wnt-7a), as well as frizzled receptors (Fzd-2 and Fzd-3), are downregulated in the aged human brain [ 44 ]. A study conducted by Inestrosa et al [ 45 ] revealed that soluble endogenous inhibitors of the Wnt signalling pathway increase in an age-dependent manner in both the hippocampus and cortex of Octodon degus . In addition, they reported that age-related Wnt signalling defects were recovered by andrographolide treatment in O. degus [ 45 ].…”

“…A study conducted by Inestrosa et al [ 45 ] revealed that soluble endogenous inhibitors of the Wnt signalling pathway increase in an age-dependent manner in both the hippocampus and cortex of Octodon degus . In addition, they reported that age-related Wnt signalling defects were recovered by andrographolide treatment in O. degus [ 45 ].…”