Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change

Abstract

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-β Aβ40 and Aβ42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1-2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aβ40/42 an enigma. Here we explored regulation of Aβ40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aβ40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aβ40 production. Conversely, single spikes did not alter basal PS1 conformation and Aβ40/42. Burst-induced PS1 conformational shift was mediated by means of Ca(2+)-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aβ40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aβ40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

“…This is consistent with the composition of Ab species reported for human CSF, in which Ab40 is the dominant isoform (Murphy et al, 1999). The relative production of Ab40 and Ab42 is probably regulated through changes in the g-secretase cleavage site (Murphy et al, 1999;Dolev et al, 2013). Second, the model included an Ab o pool in the brain for Ab42 but not Ab40.…”

Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase

“…Reduced Ab42/total Ab ratio in heterozygous mouse brain suggests that partial inhibition of CALM function could be enough to prevent the development of AD with minimal side effects. In this regard, it is noteworthy to mention that Ca 2 þ -dependent synaptic vesicle exocytosis has been shown to modulate PS1 conformation and the Ab42 production ratio 47 . As CALM is essential to the endocytic pathway of synaptic vesicles 48 , CALM would be a critical regulator of neuronal activity-dependent Ab42 production ratio.…”

Aβ42 oligomers selectively disrupt neuronal calcium release

“…Indeed, conditioned media from cortical neuronal cultures (DIV 12e17), obtained from both types of mice, failed to mimic the Ab42o effects described (M.J. Kipanyula and C. Fasolato, data not shown), and it is known that the extracellular fluids of neuronal cultures or brain slices obtained from APP mice contain Ab42 at nanomolar concentrations (Hudry et al, 2012;Waters, 2010). Conversely, higher amounts of Ab42o can accumulate at the spine level where they are released during synaptic activity in a Ca 2þ -dependent way (Dolev et al, 2013;Kamenetz et al, 2003). Interestingly, in this work, the effects on neuronal Ca 2þ stores induced by Ab42o were abolished by TTX or TeNT pretreatment, that is, under conditions that block neuronal excitability and cycling of synaptic vesicles.…”