Small molecule cognitive enhancer reverses age-related memory decline in mice
- Department of Physical Therapy and Rehabilitation Science, University of California at San Francisco, United States
- Brain and Spinal Injury Center, University of California at San Francisco, United States
- Department of Pathology, University of California at San Francisco, United States
- Biochemistry and Biophysics, University of California at San Francisco, United States
- Fundación Ciencia & Vida, Chile
- Howard Hughes Medical Institute, University of California at San Francisco, United States
- Department of Neurological Surgery, University of California at San Francisco, United States
- Weill Institute for Neuroscience, University of California at San Francisco, United States
- Kavli Institute of Fundamental Neuroscience, University of California at San Francisco, United States
Figures
Figure 1 with 2 supplements
ISRIB resets the ISR in the brain of old mice.
(A) Experimental dosing scheme: ISRIB treatment denoted by syringes (three injections). (B) ISRIB treatment reduced ATF4 protein levels chronically 18 days after ISRIB treatment was complete. …
Figure 1—figure supplement 1
ISRIB downregulates ATF4 during administration.
The impact of ISRIB on known ISR activation pathways was investigated by western blot analysis of brain lysates after 3 ISRIB injections. (A) Raw western blot data. Each lane represents an …
Figure 1—figure supplement 2
ISRIB down-regulates the ISR in the brain of old mice.
The impact of ISRIB on known ISR kinases and activation pathways was investigated by western blot analysis of brain lysates (raw western blot data) at day 20. (A) ATF4 (B) p-GCN2, p-PKR, p-PERK. …
Figure 2 with 2 supplements
Inhibition of the ISR reverses age-induced decline in spatial, working, and episodic memory.
(A) Experimental Design: Old (~19 months) animals underwent behavioral analysis in a radial arm water maze (RAWM) and a delayed matching to place paradigm (DMP). ISRIB or vehicle administration (2.5 …
Figure 2—figure supplement 1
ISR inhibitors relieve age-induced deficits in spatial learning.
RAWM was used to measure age-induced deficits in spatial learning. Animals ran two blocks (three trials/block) on each learning day. (A) Old animals performed significantly worse that young animals. …
Figure 2—figure supplement 2
ISRIB reduces age-induced memory deficits in female mice.
RAWM was used to measure age-induced deficits in learning and memory. ISRIB treatment improved memory 1 week after administration in female rodents. Student t-test. Old female n = 12; Old female + …
Figure 3 with 2 supplements
ISRIB treatment alleviates age-associated changes in CA1 pyramidal neuron function and structure.
(A) Left: Image of pipette patched onto CA1 neuron in sagittal slice of hippocampus. Right: Representative traces from hippocampal CA1 pyramidal neurons from old animals treated with either vehicle …
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Figure 3—source data 1
List of electrophysiology reagents.
Column 1 – reagent name; Column 2 – Company of purchase; Column 3 – Catalog number.
- https://cdn.elifesciences.org/articles/62048/elife-62048-fig3-data1-v2.docx
Figure 3—figure supplement 1
Age and ISRIB treatment do not modify other passive or active intrinsic membrane properties in CA1 pyramidal neurons.
(A) Representative traces from CA1 pyramidal neurons showing the membrane potential response to a 250 pA current injection in neurons from old animals treated with either vehicle (light blue) or …
Figure 3—figure supplement 2
Age and ISRIB treatment do not affect spontaneous excitatory post-synaptic currents (sEPSC) in CA1 pyramidal neurons.
(A) Representative whole cell voltage-clamp recordings showing sEPSCs from CA1 pyramidal neurons from old animals treated with either vehicle (light blue) or ISRIB (dark blue) or young animals …
Figure 4 with 1 supplement
Age-induced inflammatory tone is reduced following ISRIB treatment.
Inflammatory genes were investigated in the hippocampus of young and old mice by qPCR analysis. (A-C) ISRIB administration reversed age-induced increases in Rtp4, Ifit1, and Gbp10. (A) Rtp4, One-way …
Figure 4—figure supplement 1
ISRIB administration does not impact glial cell activation.
(A) ISRIB administration scheme. (B–G) Glial cell was quantified in the stratum radiatum of the CA1 region of the dorsal hippocampus from old Thy1-YFP-H mice. GFAP was used to measure astrocyte …
Figure 5 with 1 supplement
ISRIB treatment resets age-related ISR activation.
(A) A significant negative correlation was measured between cognitive performance on day 2 of the RAWM (errors) and Ppp1r15a mRNA expression. Linear regression was measured by Pearson R correlation, …
Figure 5—figure supplement 1
ISRIB treatment breaks age-related ISR activation.
The impact of ISRIB on p-eIF2 was investigated by western blot analysis of brain lysates after three ISRIB injections. Raw western blot data. Each lane represents an individual animal brain extract.
Tables
Table 1
Impact of age and ISRIB on mRNA expression in the hippocampus.
Inflammatory, ISR mediators and neuronal health targets were investigated by qPCR analysis of hippocampal lysates after two ISRIB injections. Columns: (i) mRNA targets (ii) Young group mean ± SEM …
| TARGET | Young | Old | Old + ISRIB | ANOVA | Btw Groups | n: Yg/Old/Old + ISRIB |
|---|---|---|---|---|---|---|
| Ccl2 | 1.0 ± 0.1 | 2.3 ± 0.4 | 1.6 ± 0.1 | F = 5.6* | Yg v Old** | 8/7/7 |
| Cd11b | 1.0 ± 0.0 | 1.0 ± 0.0 | 1.2 ± 0.0 | F = 6.6** | Yg v Old + ISRIB** Old v Old + ISRIB* | 8/7/8 |
| Il1-β | 1.1 ± 0.1 | 1.4 ± 0.1 | 1.7 ± 0.1 | F = 3.6* | Yg v Old + ISRIB* | 8/7/8 |
| Tnf α | 1.0 ± 0.1 | 1.6 ± 0.3 | 2.1 ± 0.4 | F = 2.7 | 7/7/8 | |
| Il-6 | 1.1 ± 0.2 | 1.8 ± 0.1 | 1.8 ± 0.2 | F = 4.1* | Yg v Old* | 8/7/8 |
| Il-10 | 1.0 ± 0.1 | 1.4 ± 0.2 | 1.5 ± 0.2 | F = 1.1 | 7/7/7 | |
| Irf7 | 1.0 ± 0.1 | 1.4 ± 0.1 | 1.2 ± 0.1 | F = 1.5 | 8/7/8 | |
| Ifitm3 | 1.0 ± 0.0 | 1.2 ± 0.1 | 1.0 ± 0.0 | F = 0.8 | 8/7/8 | |
| Isg15 | 1.0 ± 0.0 | 1.3 ± 0.1 | 1.2 ± 0.0 | F = 2.0 | 8/7/7 | |
| Ifi204 | 1.1 ± 0.2 | 1.4 ± 0.2 | 1.5 ± 0.1 | F = 1.2 | 6/7/7 | |
| Gbp5 | 1.0 ± 0.0 | 1.2 ± 0.1 | 1.1 ± 0.0 | F = 2.6 | 8/7/8 | |
| Oasl1 | 1.0 ± 0.0 | 1.8 ± 0.3 | 0.9 ± 0.1 | F = 4.9* | Yg v Old*; Old v Old + ISRIB* | 8/7/8 |
| Ophn1 | 1.0 ± 0.0 | 0.9 ± 0.0 | 1.1 ± 0.0 | F = 1.8 | 8/7/8 | |
| Bdnf | 1.0 ± 0.0 | 0.9 ± 0.0 | 1.0 ± 0.0 | F = 2.7 | 8/7/8 | |
| Gadd34 | 1.0 ± 0.0 | 0.8 ± 0.0 | 0.9 ± 0.0 | F = 1.8 | 7/7/8 | |
| Pkr | 1.0 ± 0.0 | 1.0 ± 0.0 | 1.1 ± 0.0 | F = 1.0 | 8/7/8 |
