The β-Secretase BACE1 in Alzheimer’s Disease

Abstract

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.

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…Neurogranin is a small neuron-specific and post-synaptic protein abundantly expressed in the brain, especially in the hippocampal and cerebrocortical dendritic spine [ 66 , 67 , 68 ]. Neurogranin has been found to play key roles in synaptic plasticity and long-term potentiation as a major regulator of the calcium-binding protein calmodulin and of calcium-signal transduction and memory formation [ 66 , 67 , 68 , 69 ]. Autopsy studies revealed a possible correlation between neurogranin and AD, as analyses showed reduced levels of neurogranin in brains and increased levels in the CSF of AD patients [ 68 ].…”

“…Moreover, it has been shown to be able to detect early-stage pathological changes, even in the MCI stage, and predict and monitor AD-related cognitive decline, thus serving as a promising pre-symptomatic biomarker [ 67 , 68 ]. BACE1 (β-site APP cleaving enzyme-1) is an aspartyl protease discovered in 1999, which, by contrast to other peptidases of the pepsin family, such as cathepsin D and E, is a type I transmembrane protein [ 69 , 71 ]. Commonly expressed in neurons, oligodendrocytes and astrocytes, BACE1 is more abundantly found within certain neuronal cell types [ 69 ].…”

“…BACE1 (β-site APP cleaving enzyme-1) is an aspartyl protease discovered in 1999, which, by contrast to other peptidases of the pepsin family, such as cathepsin D and E, is a type I transmembrane protein [ 69 , 71 ]. Commonly expressed in neurons, oligodendrocytes and astrocytes, BACE1 is more abundantly found within certain neuronal cell types [ 69 ]. The generation of Aβ monomeric forms is dependent upon the activity of BACE1, this being directly related to synaptic functions, plasticity and homeostasis [ 69 , 72 ].…”

“…Commonly expressed in neurons, oligodendrocytes and astrocytes, BACE1 is more abundantly found within certain neuronal cell types [ 69 ]. The generation of Aβ monomeric forms is dependent upon the activity of BACE1, this being directly related to synaptic functions, plasticity and homeostasis [ 69 , 72 ]. Studies have shown the significantly increased concentrations and activity rates of BACE1 in AD brains and CSF, which is thought to cause a vicious cycle by producing Aβ peptides near synapses [ 69 , 72 , 73 , 74 , 75 ].…”

Interaction between Cognitive Reserve and Biomarkers in Alzheimer Disease

“…The multicenter study conducted by Hulsteart et al established cutoff values of 1 for IATI (IATI < 1: Suggestive for AD; IATI > 1: Normal) and 61 ρg/mL for p-tau. Several authors then used these parameters in their studies, finding sensitivity values up to 94% in the diagnosis of AD; the lowest levels of specificity were found, however, in the diagnosis of VaD (48%) [ 26 ]. Within the population affected by AD there is a subgroup recognized as SNAP (suspected non-AD pathophysiology) [ 21 ], in which subjects have normal amyloid markers, but show signs of neurodegeneration different from AD.…”