Amyloid-β (Aβ) plaque deposition in specific brain regions is a major pathological hallmark of Alzheimer’fs disease (AD). However, the mechanism underlying the regional vulnerability to Aβ deposition in AD is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ levels in multiple brain regions of APP transgenic mice prior to plaque deposition were commensurate with the degree of subsequent plaque deposition and to the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissae stimulation increased ISF Aβ, and unilateral vibrissae deprivation decreased ISF Aβ and lactate levels in contralateral barrel cortex. Long term unilateral vibrissae deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in AD.

Aggregation of amyloid-β (Aβ) in the brain begins to occur years prior to the clinical onset of Alzheimer’s disease (AD). Prior to Aβ aggregation, levels of extracellular, soluble interstitial fluid (ISF) Aβ, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep declines with aging and to a greater extent in AD. How sleep quality amount as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation are not well understood. We report that a normal sleep-wake cycle and diurnal fluctuation of ISF Aβ is present in the brain of APPswe/PS1δE9 mice before Aβ plaque formation. Following plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid (CSF) Aβ in young adult humans with presenilin mutations was also markedly attenuated with Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ42 normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system appear to be functional and biochemical markers respectively of Aβ-associated pathology that should be explored in humans diagnostically prior to and following symptom onset and in response to treatment.

Summary Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.