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Diabetes is a major risk factor for Alzheimer’s disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin’s effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2’s potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity.
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BDNF, endurance activity, and mechanisms underlying the evolution of hominin brains
Abstract ObjectivesAs a complex, polygenic trait, brain size has likely been influenced by a range of direct and indirect selection pressures for both cognitive and non‐cognitive functions and capabilities. It has been hypothesized that hominin brain expansion was, in part, a correlated response to selection acting on aerobic capacity (Raichlen & Polk, 2013). According to this hypothesis, selection for aerobic capacity increased the activity of various signaling molecules, including those involved in brain growth. One key molecule is brain‐derived neurotrophic factor (BDNF), a protein that regulates neuronal development, survival, and plasticity in mammals. This review updates, partially tests, and expands Raichlen and Polk's (2013) hypothesis by evaluating evidence for BDNF as a mediator of brain size. DiscussionWe contend that selection for endurance capabilities in a hot climate favored changes to muscle composition, mitochondrial dynamics and increased energy budget through pathways involving regulation of PGC‐1α and MEF2 genes, both of which promote BDNF activity. In addition, the evolution of hairlessness and the skin's thermoregulatory response provide other molecular pathways that promote both BDNF activity and neurotransmitter synthesis. We discuss how these pathways contributed to the evolution of brain size and function in human evolution and propose avenues for future research. Our results support Raichlen and Polk's contention that selection for non‐cognitive functions has direct mechanistic linkages to the evolution of brain size in hominins.
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- Award ID(s):
- 1638756
- PAR ID:
- 10462717
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- American Journal of Physical Anthropology
- Volume:
- 168
- Issue:
- S67
- ISSN:
- 0002-9483
- Page Range / eLocation ID:
- p. 47-62
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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