Alzheimer's disease (AD) is characterized by a dramatic loss of old consolidated memory. Our study proposes a new hypothesis that neurodegeneration affects mechanisms of memory reconsolidation, leading to the weakening of old memories when they are retrieved in the diseased brain, resulting in gradual self-degradation of the consolidated memory. Testing this hypothesis in transgenic 5xFAD mice we found that their contextual memory was impaired following retrieval compared to control animals. To protect memory during reconsolidation, we administered the NMDA receptor antagonist MK-801 which is known to inhibit memory labilization. MK-801 protected memory from deterioration, which confirms our hypothesis. Interestingly, MK-801 had no effect on memory reconsolidation in 2-year-old normal mice, indicating that its effect is specific to amyloid pathology. We then used c-Fos expression mapping of brain activity during contextual memory retrieval following reconsolidation in 5xFAD mice, in normally aged mice, and after MK-801 administration. 5xFAD mice showed increased activation in the frontal cortex and hippocampus compared to control C57 Bl/6 mice. MK-801 increased activity in prelimbic cortex during memory retrieval in all groups. Its protective effect on memory in 5xFAD mice, manifested by increased freezing, was accompanied by increased activation of the amygdala and CA1. This was in contrast to the effect of MK-801 in control mice, where it reduced amygdala activity and impaired memory, as evidenced by reduced freezing. Our study demonstrates a potential mechanism for old memory impairment in Alzheimer's disease and highlights potential strategies to protect this pathology. Supported by RSF 20-15-00283.