Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo

Abstract

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

“…Confirmation of presynaptic localization of oligomers by electron microscope would be optimal; however, detection of intraneuronal, particularly oligomeric, Ab is limited by the technical difficulty of detecting Ab antigens, which are hydrophobic and difficult to detect by conventional immunocytochemical methods, especially in postmortem tissue. 67 On the basis of previous and current results, we posit that most synaptosomal Ab represents an intraterminal pool largely localized within endosomal and autophagic vesicles, consistent with a strong literature showing synaptic release of Ab 25,68,69 and disruption of autophagy in AD. 69e72 Relatively few examples in the literature have found cellular or pathologic factors associated with cognitive protection in subjects with AD pathology.…”

“…8,18e21 In humans, electron microscopic studies have documented synapse-associated Ab and tau, 22,23 and much work documents activity-dependent release of synaptic Ab into interstitial fluid, which drives local Ab deposition in human subjects and in rodents. 4,24,25 Of importance, most synapse-associated Ab in cortical synapses of AD patients consists of soluble oligomeric species, 26 and synaptic tau pathology in AD also includes accumulations of SDS-stable tau oligomers. 27e31 With the use of synaptosomes (resealed nerve terminals) from the cortex of postmortem human subjects and a transgenic rat model of AD, the present experiments were aimed at determining the sequence of appearance of Ab and hyperphosphorylated tau (p-tau) pathology in synaptic terminals.…”

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells

“…Growing evidence exists that native Aβ, which is produced during neuronal activity (Cirrito et al ., 2005), may subserve physiological functions (reviewed in Giuffrida et al ., 2010; Kepp, 2016). In particular, endogenous Aβ seems to be relevant for the control of synaptic activity and memory formation (Puzzo et al ., 2011; Piccini et al ., 2012), via the activation of α‐7‐nAChRs (Calabrese, 2001).…”

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…However, the mechanism by which memantine regulates amyloid metabolism is not clear. It has been shown that increased neuronal activity leads to increased APP production, a likely precursor to Ab plaque formation (Cirrito et al, 2005). Thus, blockade of NMDA receptors by memantine could reduce neuronal activity and subsequently lower APP production.…”