| First Author | Pignataro A | Year | 2019 |
| Journal | Biol Psychiatry | Volume | 86 |
| Issue | 3 | Pages | 185-195 |
| PubMed ID | 30528194 | Mgi Jnum | J:281401 |
| Mgi Id | MGI:6378703 | Doi | 10.1016/j.biopsych.2018.10.018 |
| Citation | Pignataro A, et al. (2019) Activity-Induced Amyloid-beta Oligomers Drive Compensatory Synaptic Rearrangements in Brain Circuits Controlling Memory of Presymptomatic Alzheimer's Disease Mice. Biol Psychiatry 86(3):185-195 |
| abstractText | BACKGROUND: A consistent proportion of individuals at risk for Alzheimer's disease show intact cognition regardless of the extensive accumulation of amyloid-beta (Abeta) peptide in their brain. Several pieces of evidence indicate that overactivation of brain regions negative for Abeta can compensate for the underactivation of Abeta-positive ones to preserve cognition, but the underlying synaptic changes are still unexplored. METHODS: Using Golgi staining, we investigate how dendritic spines rearrange following contextual fear conditioning (CFC) in the hippocampus and amygdala of presymptomatic Tg2576 mice, a genetic model for Abeta accumulation. A molecular biology approach combined with intrahippocampal injection of a gamma-secretase inhibitor evaluates the impact of Abeta fluctuations on spine rearrangements. RESULTS: Encoding of CFC increases Abeta oligomerization in the hippocampus but not in the amygdala of Tg2576 mice. The presence of Abeta oligomers predicts vulnerability to network dysfunctions, as low c-Fos activation and spine maturation are detected in the hippocampus of Tg2576 mice upon recall of CFC memory. Rather, enhanced c-Fos activation and new spines are evident in the amygdala of Tg2576 mice compared with wild-type control mice. Preventing Abeta increase in the hippocampus of Tg2576 mice restores CFC-associated spine changes to wild-type levels in both the hippocampus and amygdala. CONCLUSIONS: Our study provides the first evidence of neural compensation consisting of enhanced synaptic activity in brain regions spared by Abeta load. Furthermore, it unravels an activity-mediated feedback loop through which neuronal activation during CFC encoding favors Abeta oligomerization in the hippocampus and prevents synaptic rearrangements in this region. |
