Journal article
Age-Related Alterations in the Expression of Mesencephalic Astrocyte-derived Neurotrophic Factor in the Brain and Their Impact on Neurobehavioral Functions
Mechanisms of ageing and development, Vol.228, 112125
12/2025
DOI: 10.1016/j.mad.2025.112125
PMCID: PMC12646511
PMID: 41265659
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. The ER is central to protein synthesis, folding, degradation and secretion (proteostasis), and experiences considerable stress in neurodegenerative diseases (NDDs), which activates the unfolded protein response (UPR). Aging, the primary risk factor for NDDS, is associated with impaired ER function. MANF is shown to be protective in various experimental models of NDDs. We hypothesized that the expression of MANF in the brain declines with age, which may increase the vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in a sex-specific manner.
Details
- Title: Subtitle
- Age-Related Alterations in the Expression of Mesencephalic Astrocyte-derived Neurotrophic Factor in the Brain and Their Impact on Neurobehavioral Functions
- Creators
- Di Hu - University of IowaWen Wen - University of IowaHui Li - University of Iowa, PathologyZuohui Zhang - University of IowaHong Lin - University of IowaJia Luo - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: jia-luo@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Mechanisms of ageing and development, Vol.228, 112125
- DOI
- 10.1016/j.mad.2025.112125
- PMID
- 41265659
- PMCID
- PMC12646511
- NLM abbreviation
- Mech Ageing Dev
- ISSN
- 1872-6216
- eISSN
- 1872-6216
- Publisher
- Elsevier
- Grant note
- National Institutes of Health (NIH): AA017226, AA015407
This work was supported by the National Institutes of Health (NIH) grants AA017226 and AA015407.
- Language
- English
- Electronic publication date
- 11/18/2025
- Date published
- 12/2025
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Neuroscience and Pharmacology
- Record Identifier
- 9985033765202771
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