The non-amyloidogenic pathway: structure and function of alpha-secretases

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• The amyloid cascade hypothesis is the leading theory for Alzheimer's disease (AD) pathogenesis.
• Amyloid precursor protein (APP) cleavage by alpha-secretase produces neuroprotective soluble APPsalpha, which is decreased in AD patients' cerebrospinal fluid.
• ADAM-10, ADAM-17 (TACE), and ADAM-9 are candidate alpha-secretases involved in APP processing.

Purpose of the Study:

• To review the evidence for ADAM-10, ADAM-17, and ADAM-9 acting as physiologically relevant alpha-secretases.
• To highlight the role of ADAM-10 as an alpha-secretase in vivo using a transgenic mouse model for AD.
• To discuss the potential of up-regulating alpha-secretases as a therapeutic strategy for AD.

Main Methods:

• Review of existing scientific literature on APP processing and alpha-secretase function.
• Analysis of data from transgenic mouse models for Alzheimer's disease.
• Discussion of pharmacological approaches for modulating alpha-secretase activity.

Main Results:

• ADAM-10 has been demonstrated to function as an alpha-secretase in vivo in a transgenic mouse model for AD.
• Evidence supports the roles of ADAM-10, ADAM-17, and ADAM-9 as potential alpha-secretases.
• Decreased levels of neuroprotective soluble APPsalpha in AD patients suggest a link to disease progression.

Conclusions:

• ADAM-10 is a key alpha-secretase in vivo, playing a critical role in APP processing.
• Modulating alpha-secretase activity, particularly ADAM-10, presents a promising therapeutic avenue for Alzheimer's disease.
• Further research into pharmacological up-regulation of alpha-secretases could lead to novel AD treatments.