Abstract
With the increase of life span, nonpathological age-related memory decline is affecting an increasing number of people. However, there is evidence that age-associated memory impairment only suspends, rather than irreversibly extinguishes, the intrinsic capacity of the aging nervous system for plasticity (1). Here, using a molluscan model system, we show that the age-related decline in memory performance can be reversed by administration of the pituitary adenylate cyclase activating polypeptide (PACAP). Our earlier findings showed that a homolog of the vertebrate PACAP38 and its receptors exist in the pond snail (Lymnaea stagnalis) brain (2), and it is both necessary and instructive for memory formation after reward conditioning in young animals (3). Here we show that exogenous PACAP38 boosts memory formation in aged Lymnaea, where endogenous PACAP38 levels are low in the brain. Treatment with insulin-like growth factor-1, which in vertebrates was shown to transactivate PACAP type I (PAC1) receptors (4) also boosts memory formation in aged pond snails. Due to the evolutionarily conserved nature of these polypeptides and their established role in memory and synaptic plasticity, there is a very high probability that they could also act as “memory rejuvenating” agents in humans.
Highlights
Journals of Gerontology: BIOLOGICAL SCIENCES Cite journal as: J Gerontol A Biol Sci Med Sci doi:10.1093/gerona/glu068
Our earlier findings showed that a homolog of the vertebrate PACAP38 and its receptors exist in the pond snail (Lymnaea stagnalis) brain [2], and it is both necessary and instructive for memory formation after reward conditioning in young animals [3]
RbAp48 is known to interact with a complex of CREB binding protein (CBP, a histone acetyl transferase) and phosphorylated CREB1 [6] and it was hypothesized that enhancement of the PKA-CREB1-CBP pathway and the RbAp48 protein could be a target for therapeutic interventions targeting agerelated memory loss [5]
Summary
Journals of Gerontology: BIOLOGICAL SCIENCES Cite journal as: J Gerontol A Biol Sci Med Sci doi:10.1093/gerona/glu. Using a molluscan model system, we show that the age-related decline in memory performance can be reversed by administration of the pituitary adenylate cyclase activating polypeptide (PACAP). Our earlier findings showed that a homolog of the vertebrate PACAP38 and its receptors exist in the pond snail (Lymnaea stagnalis) brain [2], and it is both necessary and instructive for memory formation after reward conditioning in young animals [3]. Treatment with insulin-like growth factor-1, which in vertebrates was shown to transactivate PACAP type I (PAC1) receptors [4] boosts memory formation in aged pond snails. Upregulation of RbAp48 in the dentate gyrus of aged wild-type mice ameliorated age-related hippocampus-based memory loss [5]. PACAP38 acts through specific PAC1, VPAC1 and VPAC2 receptors, but PAC1 has the largest affinity to the polypeptide [14]
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