Beneficial effects of synaptic activity on synapses correlate more with intraneuronal Aβ than with plaques

Abstract

A central question in Alzheimer's disease (AD) research is what role synaptic activity plays in the disease process. Synaptic activity induces Aβ secretion (Kamenetz, 2003; Cirrito, 2005), and extracellular Aβ is known to be toxic. On the other hand, epidemiological studies support that higher education levels and intellectual occupations reduce risk of AD; moreover, we recently showed that synaptic activity can reduce intraneuronal Aβ and protect synapses (Tampellini, 2009). Reduced synaptic activity in vivo decreases plaques (Kang, 2009) but increases intraneuronal Aβ (Tampellini, 2009). We now investigate what occurs to synaptic proteins under these conditions. We explore the effects of synaptic activity on Aβ and synapses in vitro with time in culture and in vivo with aging in AD transgenic and wild-type mice. Synaptic activation is induced in Tg2576 neurons at 12 and 19 days in vitro (DIV) by glycine-induced chemical LTP. Unilateral whisker removal is used to modulate synaptic activity in the brains of AD transgenic (Tg19959) and wild-type mice. Aβ is assayed by Western blot, ELISA and immunofluorescence. Levels of synaptic proteins are quantified by immunofluorescence. In vitro data show that, in contrast to 12DIV, synaptic activation fails to reduce intraneuronal Aβ and recovery of PSD-95 back to wild-type levels in 19DIV Tg2576 neurons. Chronic synaptic inhibition reduces amyloid plaques and increases intraneuronal Aβ in the deafferented barrel cortex of Tg19959 mice. However, levels of synaptophysin and PSD-95 are reduced in the barrel cortex corresponding to whisker removal compared to the ipsilateral side. We provide evidence that synaptic activity can reduce Aβ levels and protect synapses of transgenic neurons at 12 but not at 19DIV. The differences observed between 12 and 19DIV reinforce our hypothesis that under normal conditions of synaptic activity intracellular and secreted Aβ are efficiently cleared, whereas with aging and progressive intraneuronal Aβ accumulation, the cellular machinery involved in Aβ clearance becomes impaired. Understanding how synaptic activity modulates Aβ homeostasis and synapses as a function of time/age could be critical in better understanding the pathogenesis of AD.