Consequences of Inhibiting Amyloid Precursor Protein Processing Enzymes on Synaptic Function and Plasticity

[摘要] Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregatedβ-amyloid (Aβ) peptides. It is now recognized that soluble Aβoligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβis produced by a sequential cleavage of amyloid precursor protein (APP) by the activity ofβ- andγ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβalters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβgeneration. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβitself may have normal physiological functions which are disrupted by abnormal accumulation of Aβduring AD pathology. This interpretation suggests that AD therapeutics targeting theβ- andγ-secretases should be developed to restore normal levels of Aβor combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

[学科分类] 精神健康和精神病学