Increased expression of the amyloid precursor β‐secretase in Alzheimer's disease

Holsinger, R. M. Damian; McLean, Catriona; Beyreuther, Konrad; Masters, Colin L.; Evin, Geneviève

doi:10.1002/ana.10208

Cited by 518 publications

(418 citation statements)

References 19 publications

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“…We next asked whether the increased localization of C99 in the MAM also occurred in the context of AD, as tissues from AD patients and animal models show increases in this fragment (Holsinger et al , 2002). We measured C99 levels by Western blot in homogenates from embryonic cortical neurons from WT and PS1‐KI M146V mouse brain (Guo et al , 1999) (Appendix Fig S2F), as well as from cells from AD patients and controls (Appendix Fig S2G).…”

Section: Resultsmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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Section: Resultsmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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“…Thus, the initial cleavage of APP by BACE is critical for the formation of the 40 or 42 aminoacids-long Ab peptides (Ab and Ab ), which deposit as fibrillar amyloid in the senile plaques; it has been shown that BACE activity increases with age and it is elevated in AD brains ( [99,138]). Amyloidogenic peptides were shown to play a major role in brain neurotoxicity, however the molecular mechanisms remain to be clearly defined.…”

Section: Alzheimer's Disease and Neuroinflammationmentioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

262

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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“…Ab 00/6 was raised to human BACE CT (485-501) [23]. NCT, PEN-2 and APH-1 antibodies were affinity-purified using immunizing peptide coupled to SulfoLink Coupling Gel (Pierce).…”

Section: Antibodiesmentioning

confidence: 99%

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

Culvenor

Ilaya

Ryan

et al. 2003

European Journal of Biochemistry

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The presenilin proteins are required for intramembrane cleavage of a subset of type 1 membrane proteins including the Alzheimer's disease amyloid precursor protein. Previous studies indicate presenilin proteins form enzymatically active high molecular mass complexes consisting of heterodimers of N‐ and C‐terminal fragments in association with nicastrin, presenilin enhancer‐2 and anterior pharynx defective‐1 proteins. Using Blue Native gel electrophoresis (BN/PAGE) we have studied endogenous presenilin 1 complex mass, stability and association with nicastrin, presenilin enhancer‐2 and anterior pharynx defective‐1. Solubilization of mouse or human brain membranes with dodecyl‐d‐maltoside produced a 360‐kDa species reactive with antibodies to presenilin 1. Presenilin 1 complex levels were high in embryonic brain. Complex integrity was sensitive to Triton X‐100 and SDS, but stable to reducing agent. Addition of 5 m urea caused complex dissolution and nicastrin to migrate as a subcomplex. Nicastrin and presenilin enhancer‐2 were detected in the presenilin 1 complex following BN/PAGE, electroelution and second‐dimension analysis. Anterior pharynx defective‐1 was detected as an 18‐kDa form and 9‐kDa C‐terminal fragment by standard SDS/PAGE of mouse tissues, and as a predominant 36‐kDa band after presenilin 1 complex second‐dimension analysis. Membranes from brain cortex of Alzheimer's disease patients, or from cases with presenilin 1 missense mutations, indicated no change in presenilin 1 complex mobility. Higher molecular mass presenilin 1‐reactive species were detected in brain containing presenilin 1 exon 9 deletion mutation. This abnormality was confirmed using cells transfected with the same presenilin deletion mutation.

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Increased expression of the amyloid precursor β‐secretase in Alzheimer's disease

Cited by 518 publications

References 19 publications

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

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