BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-b (Ab), including Ab 42 , which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Ab production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Ab and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Ab in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.

Compared with NMDA receptor-dependent LTP, much less is known about the mechanism of induction of NMDA receptor-independent LTP; the most extensively studied form of which is mossy fiber LTP in the hippocampus. In the present study we show that Ca2+-induced Ca2+ release from intracellular stores is involved in the induction of mossy fiber LTP. This release also contributes to the kainate receptor-dependent component of the pronounced synaptic facilitation that occurs during high-frequency stimulation. We also present evidence that the trigger for this Ca2+ release is Ca2+ permeation through kainate receptors. However, these novel synaptic mechanisms can be bypassed when the Ca2+ concentration is raised (from 2 to 4 mM), via a compensatory involvement of L-type Ca2+ channels. These findings suggest that presynaptic kainate receptors at mossy fiber synapses can initiate a cascade involving Ca2+ release from intracellular stores that is important in both short-term and long-term plasticity.

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