Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

Stockley, John H.; Ravid, Rivka; O’Neill, Cora

doi:10.1016/j.febslet.2006.10.076

Cited by 47 publications

(55 citation statements)

References 52 publications

(117 reference statements)

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“…First, increased BACE protein levels and activity in postmortem AD brain [54,162] are linked to increased γ-secretase cleavage of AβPP [163] and correlate with oxidative stress levels [164]. Endogenously and exogenously-induced ROS overproduction increases both BACE1 and PS1 expression and activity [165][166][167][168], which are mediated through the activation of the JNK pathway [169][170][171] and results in increased Aβ production [161,172].…”

Section: Secretase Enzyme and Mitochondrial Dysfunctionmentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.

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Section: Secretase Enzyme and Mitochondrial Dysfunctionmentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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“…Studies comparatively examining BACE1 levels have also, for the most part, detected increased BACE1 protein levels to varying degrees in AD cases compared to controls [103,[105][106][107][108]. However, some studies have detected unchanged BACE1 levels in AD [102,109], with one study from our group detecting significantly decreased levels of the major mature BACE1 isoform, which correlated strongly with synaptophysin loss, and severity of neurofibrillary pathology in the disease [101]. A recent study found that increased BACE1 levels were only apparent in a subset (~30%) of AD cases [108].…”

Section: Bace1 Levels and B-secretase Activity In Normal And Ad Brainmentioning

confidence: 82%

“…In addition, analysis of b-secretase enzyme kinetics revealed a significant increase in the Vmax for bsecretase in AD temporal cortex, inferring changes occur at levels of altered enzyme velocity in the disease [101]. Studies comparatively examining BACE1 levels have also, for the most part, detected increased BACE1 protein levels to varying degrees in AD cases compared to controls [103,[105][106][107][108].…”

Section: Bace1 Levels and B-secretase Activity In Normal And Ad Brainmentioning

confidence: 99%

“…Importantly, all studies have consistently detected significant increases in b-secretase enzyme activity (13%-185%) in AD brain regions affected by pathology [73,[101][102][103], [for review see [104]], indicating increased BACE1 activity is most likely to be a major cause of Ab overproduction is sporadic forms of AD.…”

Section: Bace1 Levels and B-secretase Activity In Normal And Ad Brainmentioning

confidence: 99%

“…It should be noted that despite their low levels BACE2 mRNA and protein are detectable in human and rodent brain [12,25,101,118]. BACE2 knockout mice display an overall healthy phenotype [65].…”

Section: Bace2 In Brain and In Admentioning

confidence: 99%

See 2 more Smart Citations

Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease

Stockley

O’Neill

2008

Cell. Mol. Life Sci.

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The identification of the aspartic protease BACE1 (beta-secretase) was a defining event in research aimed at understanding the molecular mechanisms that underlie Alzheimer's disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting step in the production of amyloid-beta (Abeta) the principal component of plaque pathology in AD, the excessive production of which is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Abeta production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target in blocking aberrant Abeta production in AD.

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Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease

Tan

Chua

Esiri

et al. 2009

J of Neuroscience Research

106

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Alzheimer's disease (AD) is characterized by a complex neurodegenerative process affecting multiple genes and proteins in the neocortex, many of which have not been well-studied. In this study, we investigated genome-wide gene alterations in the temporal cortex of a well-characterized cohort of AD patients using a recently developed microarray platform, and compared some of the transcript changes with immunoblotting. Of the 5485 genes found to be significantly altered in AD, there were consistent patterns of changes which show that the AD transcriptome in neocortex is characterized by changes indicative of synaptic dysfunction, perturbed neurotransmission and activation of neuroinflammation. We also highlighted several genes of potential pathogenic significance which have not been well studied in AD. The current study aims to add to the growing body of knowledge relating to gene changes in AD and provide further insights into pathogenic mechanisms and potential targets of pharmacotherapy.

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Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

Cited by 47 publications

References 52 publications

The Mitochondrial Secret(ase) of Alzheimer's Disease

The Mitochondrial Secret(ase) of Alzheimer's Disease

Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease

Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease

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