α- and β-secretase: profound changes in Alzheimer’s disease

https://doi.org/10.1016/S0006-291X(02)02635-9Get rights and content

Abstract

The amyloid plaque, a neuropathological hallmark of Alzheimer’s disease, is produced by the deposition of β-amyloid (Aβ) peptide, which is cleaved from Amyloid Precursor Protein (APP) by the enzyme β-secretase. Only small amounts of Aβ form in normal brain; more typically this is precluded by the processing of APP by α-secretase. Here, we describe a decrease in α-secretase (81% of normal) and a large increase in β-secretase activity (185%) in sporadic Alzheimer’s disease temporal cortex. Since α-secretase is present principally in neurons known to be vulnerable in Alzheimer’s disease, and there is known competition between α- and β-secretase for the substrate APP, it is significant that the majority of Alzheimer samples tested here were low in α-secretase. Eighty percent of Alzheimer brains examined had an increase in β-secretase, a decrease in α-secretase, or both; which may account for the means by which the majority of people develop Alzheimer’s disease.

Section snippets

Materials and methods

Tissues. Samples of temporal cortex were obtained from 16 normal and 15 Alzheimer’s disease subjects (South West Brain Bank, UK). Tissue was taken from prospectively assessed Alzheimer patients, in whom diagnosis was confirmed by the presence of Alzheimer neuropathology; and from intellectually unimpaired subjects. Normal and Alzheimer brain tissue was selected from cases of similar mean age (73.2±8.4; 76.1±7.0: p=0.31) and post mortem delay (21.4±12.2; 26.3±9.6: p=0.22). Values are given for

Results and discussion

β-Secretase activity was increased to 185% of normal in sporadic Alzheimer patients (Fig. 1). Mean activity was 28.1±15.0 (range 5.9–48.9) for normal and 51.9±23.7 (range 15.1–93.6) for Alzheimer (p=0.003). t test was corrected for non-similar Gaussian distribution. Eight-seven per cent of Alzheimer samples had activity values above the normal mean. A sub-population (60%) of samples (differing by a SD from the mean) was increased to 235% of normal.

By contrast, mean α-secretase activity in

Acknowledgements

We are most grateful to Mrs. Sonia Matthews from the South West Brain Bank for her technical assistance. This research was supported by Bristol Research into Alzheimer’s and Care of the Elderly (BRACE) and The Gestetner Foundation.

References (18)

There are more references available in the full text version of this article.

Cited by (164)

  • Nucleotides regulate the common molecular mechanisms that underlie neurodegenerative diseases; Therapeutic implications

    2019, Brain Research Bulletin
    Citation Excerpt :

    They also reported that specific knockdown of P2X7R reduces the number of senile plaques and selective P2X7R blockers attenuate the loss of synaptic contacts in hippocampal neurons (Chen et al., 2014; Martin et al., 2018). Considering that both APP processing pathways occur in the CNS (Hardy and Selkoe, 2002), and that the non-amyloidogenic pathway is predominant in the healthy brain (Tyler et al., 2002) it would be possible to hypothesize that an abnormal increase in extracellular nucleotide concentration favouring the P2X7R signaling might be one of the main factors leading the shift to the amyloidogenic pathway in sporadic AD (Stockley and O’Neill, 2008). Over recent years, evidence has emerged suggesting that aggregated proteins spread from one cell to another, behaving like seeds that prompt protein to cause misfolding and aggregation in healthy cells (Walker and LeVine, 2012).

  • Relationship between long non-coding RNAs and Alzheimer's disease: a systematic review

    2019, Pathology Research and Practice
    Citation Excerpt :

    APP is normally cleaved by α and β secretase to sAPPα or sAPPβ, which promote neuronal growth [21]. In patients with AD, the APP is sequentially cut by α and γ secretase and converted to insoluble product which circulates in blood and promotes the same in more cells [22]. There is abundance in β sheets as against alpha helices normally.

View all citing articles on Scopus
View full text