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. 2016 Aug;44:9-21.
doi: 10.1016/j.neurobiolaging.2016.04.006. Epub 2016 Apr 21.

Insulin-like Growth Factor 2 Rescues Aging-Related Memory Loss in Rats

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Insulin-like Growth Factor 2 Rescues Aging-Related Memory Loss in Rats

Adam B Steinmetz et al. Neurobiol Aging. .
Free PMC article

Abstract

Aging is accompanied by declines in memory performance, and particularly affects memories that rely on hippocampal-cortical systems, such as episodic and explicit. With aged populations significantly increasing, the need for preventing or rescuing memory deficits is pressing. However, effective treatments are lacking. Here, we show that the level of the mature form of insulin-like growth factor 2 (IGF-2), a peptide regulated in the hippocampus by learning, required for memory consolidation and a promoter of memory enhancement in young adult rodents, is significantly reduced in hippocampal synapses of aged rats. By contrast, the hippocampal level of the immature form proIGF-2 is increased, suggesting an aging-related deficit in IGF-2 processing. In agreement, aged compared to young adult rats are deficient in the activity of proprotein convertase 2, an enzyme that likely mediates IGF-2 posttranslational processing. Hippocampal administration of the recombinant, mature form of IGF-2 rescues hippocampal-dependent memory deficits and working memory impairment in aged rats. Thus, IGF-2 may represent a novel therapeutic avenue for preventing or reversing aging-related cognitive impairments.

Keywords: Hippocampus; Insulin-like growth factor-2; Memory; Proprotein convertase; Rat; Working memory.

Conflict of interest statement

Conflict of interest: The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Decreased mature IGF-2 and increased proIGF-2 protein levels in the hippocampus of aged compared to young adult rats. (a) Western blot competition with recombinant mouse IGF-2 peptide (rmIGF-2), recombinant mouse IGF-1 peptide (rmIGF-1), recombinant human proIGF-2 peptide (rhproIGF-2), or recombinant human proIGF-1 peptide (rhproIGF-1). The band detected by anti-IGF-2 at 15 kDa is competed in dorsal hippocampal synaptoneurosomal (dHC SN) and total (dHC total) protein extracts by rmIGF-2 but not rmIGF-1, while the band detected at 20 kDa is competed by rhproIGF-2 but not rhproIGF-1. (b–d) Relative quantitative western blot analyses of dHC total or SN extracts. Data are expressed as mean percentage ± SEM of the average protein concentration found in the young adult rat group. Each densitometric value was normalized against β-actin detected on the same blot (loading control). Representative blots are shown above their respective grouped data. (b) 20 kDa proIGF-2 protein and 15 kDa IGF-2 mature protein in dHC total protein extracts (n=8–10/group) from young adult and aged rats. (c) 20 kDa proIGF-2 protein and 15 kDa IGF-2 mature protein in dHC SN extracts (n=17/group) from young adult and aged rats. (d) IGF-2 receptor (IGF-2R) levels in dHC total (n=9/group) and dHC SN extracts (n=9/group) from young and aged rats. * p<0.05, ** p<0.01.
Figure 2
Figure 2
Significant decrease of proprotein convertase 2 (PC2) enzymatic activity in the hippocampus of aged rats. (a) Data are shown as mean percentage of the protein concentration found in young adult rats. Representative bands from relative quantitative Western blot analyses are shown above their respective data. PC2 protein levels in dHC total hippocampal protein extracts and dHC SN extracts (n=9/group). (b) PC2-specific enzymatic activity taken as picomoles of 7-Amino-4-methylcoumarin released from pERTKR-AMC per minute (pmol/min) inhibited by the PC2-specific inhibitor Pro-7B2 (156–186)/CT Mouse Peptide (n=7/group). ** p<0.01.
Figure 3
Figure 3
Bilateral dorsal hippocampal IGF-2 injection given after IA training rescues aging-related long-term memory impairment. Experimental schedules are shown above their respective data. Injections (arrow) of vehicle or recombinant IGF-2 peptide immediately after training at specified shock intensities and tested at indicated time points. IA memory shown as median latencies expressed in seconds (s) (black bar within box) ± quartiles (box) and minimum/maximum values (whiskers). (a) IA memory was tested at 1 (Test 1), 14 (Test 2) and 28 days (Test 3) after training. 1 day after Test 3, generalization (Gen) was tested in a different context (n = 7–9/group). (b) IA memory was tested at 14 days after training (n = 8–11/group). (c) IA memory was tested at 14 days after training (n = 7/group). (d) IA memory was tested at 28 days after training (Test 1), and tested again at 35 days after training (Test 2). Moses test between aged vehicle and IGF-2 groups at Test 2: p=0.001; n = 10–11/group). Bonferroni-corrected non-parametric between-group comparisons or Tukey HSD tests are shown by * p<0.005, or * p<0.05, respectively.
Figure 4
Figure 4
Bilateral dorsal hippocampal injection of IGF-2 rescues the impairments of object location and spontaneous alternation memory in aged rats. Experimental schedules of the assessment of spatial location and working memory across exploration and test days are listed above (a) and (c). Injections (arrow) of vehicle or IGF-2 immediately after training (a and b) or 20 min prior to testing (c and d). (a) Percent of time spent exploring the moved object for young adult and aged rats at training, test 1, and test 2. Data are expressed as means ± SEM (n=12 per group). (b) Means ± SEM of total exploration time (in seconds, s) of both familiar and novel object locations at training, test 1, and test 2 in young adult and aged rats (c) The percent of correct alternations, expressed as means ± SEM, for young adult and aged animals that received IGF-2 or vehicle (n=12 per group). (d) Total arm entries (± SEM) during the 20 min spontaneous alternation test. * p<0.05, ** p<0.01, *** p<0.001 significance levels for Tukey HSD post hoc tests. ## p<0.01 significance for one sample t tests comparing each group to chance performance (50%). Dashed lines represent chance performance.

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