Effects of Synaptic Modulation on β-Amyloid, Synaptophysin, and Memory Performance in Alzheimer's Disease Transgenic Mice

Abstract

Accumulation of ␤-amyloid (A␤) and loss of synapses are hallmarks of Alzheimer's disease (AD). How synaptic activity relates to A␤ accumulation and loss of synapses is a current topic of major interest. Synaptic activation promotes A␤ secretion, and chronic reduction of synaptic activity reduced A␤ plaques in an AD transgenic mouse model. This suggested beneficial effects of reducing synaptic activity in AD. We now show that reduced synaptic activity causes detrimental effects on synapses and memory despite reducing plaques using two different models of chronic synaptic inhibition: deafferentation of the barrel cortex and administration of benzodiazepine. An interval of prolonged synaptic inhibition exacerbated loss of synaptophysin compared with synaptically more active brain in AD transgenic but not wild-type mice. Furthermore, an interval of benzodiazepine treatment, followed by a washout period, exacerbated memory impairment in AD transgenic mice. Exacerbation of synaptic and behavioral abnormalities occurred in the setting of reduced A␤ plaques but elevated intraneuronal A␤ immunoreactivity. These data support beneficial effects of synaptic activation on A␤-related synaptic and behavioral impairment in AD.

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…Here, we present evidence that glutamate itself, after Aβ-induced release from astrocytes, is responsible, at least in part, for triggering synaptic loss. Additionally, the effect of eNMDAR vs. sNMDAR activity on Aβ production and oligomerization (7,8,59,60) could produce a positive feedback loop whereby oligomerized Aβ induces eNMDAR activity, as shown here, and eNMDAR activity also triggers toxic Aβ generation (Fig. 7G).…”

“…Although this paradigm first was demonstrated for ischemic brain disease, accumulating evidence suggests that it also is true for neurodegenerative disorders involving protein misfolding, such as Huntington disease (3,4) and AD (7,8,59,60). Additionally, linking this dichotomy of eNMDAR vs. sNMDAR activation to synaptic integrity, we and others previously have shown that low levels of glutamate or endogenous synaptic activity may enhance dendritic spine growth (61,62).…”

The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease

“…Sleep deprivation, potentially via elevated synaptic activity, led to greater plaque pathology in AD transgenic mice [33], although intraneuronal Aβ, synapses or behavior were not examined in this study. On the other hand, diminished cerebral activity reduced plaque pathology but elevated intraneuronal Aβ and worsened synapse damage and behavioral impairment in AD transgenic mice [27]. Overall, these studies and the study by Mohajeri et al [28] support that either elevated or reduced cerebral activity can be detrimental to synapses via intraneuronal but not plaque-associated Aβ in AD transgenic mice.…”

“…Increasing evidence shows that amyloid plaques themselves are not the critical element in synapse damage, since unilateral inhibition of cortical activity in the barrel cortex of AD transgenic but not wild-type mice after whisker removal led to synapse degeneration despite plaque reduction but concomitant intraneuronal Aβ42 accumulation [27]. Similarly, excessive cerebral activity from seizures led to neurodegeneration accompanied by intraneuronal Aβ accumulation in AD transgenic compared to wild-type mice [28].…”

Investigating Amyloid β toxicity in Drosophila melanogaste

“…Both in vitro and in vivo reports have displayed that the accumulation of intracellular Aβ precedes the build up of extracellular deposits [134] and AD transgenic mice studies have reported a correlation between levels of intracellular Aβ and Aβ-related synapse damage and memory impairment. A correlation that was not observed with plaque burden [136]. It has been widely accepted that various oligomers are the most toxic assembly form responsible for pathology.…”