This paper by Tampellini and colleagues is an interesting account of amyloid precursor protein (APP) trafficking and amyloid beta (Aβ) metabolism as a result of synaptic activity. Using glycine chemical long-term potentiation (LTP) and direct depolarization with potassium, they show that intracellular Aβ levels decrease. Previous work by our group and Roberto Malinow’s group has demonstrated that synaptic activity induces Aβ generation and release from neurons (Cirrito et al., 2008; Kamenetz et al., 2003). Tampellini and colleagues’ data is entirely consistent with this model; synaptic activity increases Aβ release thereby reducing intracellular Aβ. Interestingly, Davide shows that synaptic activity also enhances neprilysin-mediated degradation of intracellular Aβ. This appears to be Aβ42-specific since intracellular Aβ40 levels still decrease in the presence of thiorphan, an inhibitor of neprilysin. This suggests that newly generated Aβ...  Read more

This paper by Tampellini and colleagues is an interesting account of amyloid precursor protein (APP) trafficking and amyloid beta (Aβ) metabolism as a result of synaptic activity. Using glycine chemical long-term potentiation (LTP) and direct depolarization with potassium, they show that intracellular Aβ levels decrease. Previous work by our group and Roberto Malinow’s group has demonstrated that synaptic activity induces Aβ generation and release from neurons (Cirrito et al., 2008; Kamenetz et al., 2003). Tampellini and colleagues’ data is entirely consistent with this model; synaptic activity increases Aβ release thereby reducing intracellular Aβ. Interestingly, Davide shows that synaptic activity also enhances neprilysin-mediated degradation of intracellular Aβ. This appears to be Aβ42-specific since intracellular Aβ40 levels still decrease in the presence of thiorphan, an inhibitor of neprilysin. This suggests that newly generated Aβ can proceed down at least two pathways: release or degradation. The mechanisms that decide Aβ’s fate are unclear and how those mechanisms would differentially affect Aβ sub-species is unknown. Additionally, the percentage of Aβ that is released as opposed to degraded intracellularly remains an open question. Like any good study, Tampellini and colleagues generate more questions than are answered.

It appears that synaptic activity can differentially affect Aβ within distinct brain compartments. Our previous work has demonstrated that synaptic vesicle exocytosis rapidly increases extracellular Aβ levels in vivo (Cirrito et al., 2005). This is a presynaptic event. Tampellini now shows that synaptic activity also affects intracellular Aβ degradation to some extent. Additionally, activation of postsynaptic receptors can also lead to signaling pathways that alter APP processing and Aβ levels. Over 15 years ago it was shown that M1 muscarinic acetylcholine receptors can reduce Aβ levels (Nitsch et al., 1992) in a PKC-dependent pathway. More recently it was shown that activation of NMDA receptors can also increase α-secretase cleavage thereby reducing Aβ generation (Hoey et al., 2009). The interplay of each of these synapse-related mechanisms will determine overall brain Aβ levels. How all of these mechanisms collectively contribute to Aβ toxicity in the setting of Alzheimer disease must still be determined.

View all comments by John Cirrito