Abstract
Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by increasing loss in memory, cognition, and function of daily living. Among the many pathologic events observed in the progression of AD, changes in amyloid β peptide (Aβ) metabolism proceed fastest, and precede clinical symptoms. BACE1 (β-secretase 1) catalyzes the initial cleavage of the amyloid precursor protein to generate Aβ. Therefore inhibition of BACE1 activity could block one of the earliest pathologic events in AD. However, therapeutic BACE1 inhibition to block Aβ production may need to be balanced with possible effects that might result from diminished physiologic functions BACE1, in particular processing of substrates involved in neuronal function of the brain and periphery. Potentials for beneficial or consequential effects resulting from pharmacologic inhibition of BACE1 are reviewed in context of ongoing clinical trials testing the effect of BACE1 candidate inhibitor drugs in AD populations.
Highlights
Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder, slowly eroding memory, cognition, and functions of daily living, inevitably culminating in death from pneumonia and infectious diseases resulting from failure to thrive, loss of fine motor skills, and incapacitation.Treatment is limited to therapeutics that alleviate symptoms of memory loss, but are effective for a relatively short duration during and after which disease progression continues
The aim of this review is to provide additional perspective and to revisit unique features of BACE1 structure and function
Inhibiting BACE1 to block amyloid β (Aβ) production would be expected to deplete the supply of nascent Aβ feeding into the modification, oligomerization and accumulation pathways, diminishing oligomeric and all forms of Aβ contributing to synaptic dysfunction and other downstream effects [127,128,129]
Summary
Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder, slowly eroding memory, cognition, and functions of daily living, inevitably culminating in death from pneumonia and infectious diseases resulting from failure to thrive, loss of fine motor skills, and incapacitation. Treatment is limited to therapeutics that alleviate symptoms of memory loss, but are effective for a relatively short duration during and after which disease progression continues. Accumulation of Aβ is one of the earliest events in the disease process, occurring to near completion 10–20 years prior to the onset of memory loss and other clinical symptoms [5]. The Aβ peptide present in amyloid plaque is approximately 36–43 amino acids in length, generated from the amyloid precursor protein (APP) by a series of proteolytic cleavages followed by a broad diversity of post-translational modifications (in this review are all collectively referred to as Aβ). BACE1 has been considered a relevant target for development of drugs to inhibit its secretase activity towards APP to thwart Aβ production and AD progression. The aim of this review is to provide additional perspective and to revisit unique features of BACE1 structure and function
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