Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated βAmyloid (A) peptides. It is now recognized that soluble A oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. A is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γSecretases, which have been iDentified as major candidate therapeutic targets of AD. This paper focuses on how A alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for A generation. Abnormalities in synaptic function resulting from the absence or inhibition of the A-producing enzymes suggest that A itself may have normal physiological functions which are disrupted by abnormal accumulation of A during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γSecretases should be Developed to restore normal levels of A or combined with measures to circumvent the associated synaptic dysfunction(s) in orDer to have minimal impact on normal synaptic function.