Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism

Abstract

Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, high levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes.

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

“…Thus, we know that differentiation and growth of axons and dendrites occurs during the first week, establishment of synaptic contacts and electric communication during the second week, wear and tear signs of stress develop during the third week, and signs of degeneration and death by apoptosis during the fourth week. Previous work from our laboratory demonstrated the gradual appearance of signs of aging/stress by the end of the third-week in culture and greater during the fourth week: that is, presence of lipofuscin granules, accumulation of reactive oxygen species, hyperphosphorylation of τ, increased stress/anti-stress activity (Akt, BCL2, pJNK, p53, and p21), reduced expression of synaptic plasticity genes, reduced synaptic activity, impaired insulin signalling, altered plasma membrane composition, and reduced activity of the proteasome/autophagosome systems ( Martin et al, 2008 , 2011 , 2014 ; Sodero et al, 2011 ; Trovò et al, 2013 ; Palomer et al, 2016 ; Benvegnù et al, 2017 ; Moreno-Blas et al, 2019 ; Martín-Segura et al, 2019b ). Therefore, these cells carry out their entire life cycle in the course of 4 wk, with the fourth week showing, consistent with this lifespan, features of dysfunction typically found in vivo aging studies.…”

p38MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects

“…26 Recent studies have provided ample evidence, supporting that the p38MAPK signaling pathway is associated with a variety of age-related diseases. [27][28][29][30][31][32] For example, according to Moreno-Cugnon et al, the elevated p38MAPK activity was associated with neural stem cell aging. 29 Chen et al suggested that RAB7 was a protective factor for intervertebral discs, which retarded the intervertebral disc degeneration by inhibiting the p38MAPK pathway.…”

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer‐Related Pain by Using Network Pharmacology and Molecular Docking Approach

“…Cholesterol, widely consisted in vivo, a precursor of neurosteroid biosynthesis, is an endogenous produced molecule that inhibits TRPV1 activity and plays an important role in the regulation of nervous system injury and disorder [ 52 ]. Little is known about its role in neuropathic pain.…”