Ex Vivo Occupancy of γ-Secretase Inhibitors Correlates with Brain β-Amyloid Peptide Reduction in Tg2576 Mice

Goldstein, Murray; Cao, Yang; Fiedler, Tracey; Toyn, Jeremy H.; Iben, Lawrence G.; Barten, Donna M.; Pierdomenico, Maria; Corsa, Jason A.; Prasad, C. V. C.; Olson, R. E.; Li, Yuwen; Zaczek, Robert; Albright, Charles F.

doi:10.1124/jpet.107.125492

Cited by 11 publications

(7 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the rat, dosing of the Tg2576 mouse with the same ␥-secretase inhibitor did not result in an A␤ rise (30) consistent with the results we obtained in cell cultures that overexpress the ␤CTF or APP Swedish mutant. This suggests that the Tg2576 mouse can exhibit a misleading degree of inhibitory activity for ␥-secretase inhibitors.…”

Section: Discussionsupporting

confidence: 79%

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

Burton

Meredith

Barten

et al. 2008

Journal of Biological Chemistry

Self Cite

119

View full text Add to dashboard Cite

The amyloid-␤ (A␤) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-␤ precursor protein (APP) through consecutive proteolytic cleavages by ␤-site APP-cleaving enzyme and ␥-secretase. Unexpectedly ␥-secretase inhibitors can increase the secretion of A␤ peptides under some circumstances. This "A␤ rise" phenomenon, the same inhibitor causing an increase in A␤ at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the A␤ rise depends on the ␤-secretase-derived C-terminal fragment of APP (␤CTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of A␤, known as "p3," formed by ␣-secretase cleavage, did not exhibit a rise. In addition to the A␤ rise, low ␤CTF or C99 expression decreased ␥-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, ␥-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of A␤ under conditions of low substrate expression. The A␤ rise was also observed in rat brain after dosing with the ␥-secretase inhibitor BMS-299897. The A␤ rise and potency shift are therefore relevant factors in the development of ␥-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the A␤ rise, including the "incomplete processing" and endocytic models, are discussed.Evidence suggests that the amyloid-␤ (A␤) 9 peptide plays a key role in Alzheimer disease. A␤ is generated by proteolytic processing of the amyloid-␤ precursor protein (APP) through consecutive cleavages by the ␤-site APP-cleaving enzyme (BACE) and ␥-secretase. APP is cleaved by BACE to form a ␤-secretase-derived C-terminal fragment of APP (␤CTF), which undergoes further cleavage by ␥-secretase to form A␤. In addition, APP is cleaved by ␣-secretase to form ␣CTF, which undergoes ␥-secretase cleavage to produce an N-terminally truncated form of A␤ known as "p3." Using the conventional amino acid numbering of A␤, BACE cleavage leads to A␤ peptides with N-terminal ends at positions 1 and 11, whereas ␣-secretase leads to p3 peptides with an N-terminal end at position 17. Cleavage of ␤CTF and ␣CTF by ␥-secretase produces a mixture of different C termini in the resulting A␤ and p3 peptides. For example, the predominant ␥-secretase cleavage of ␤CTFs at position 40 produces A␤-(1-40) and A␤-(11-40), whereas other ␥-secretase cleavage sites produce a range of less abundant A␤ peptides, such as the disease-associated A␤-(1-42) (1, 2).

show abstract

Section: Discussionsupporting

confidence: 79%

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

Burton

Meredith

Barten

et al. 2008

Journal of Biological Chemistry

Self Cite

119

View full text Add to dashboard Cite

show abstract

“…The development of preclinical AD animal models has strengthened the notion that insulin resistance, T2D, and AD are mechanistically linked (Goldstein et al, 2007; Ho et al, 2004; Pedersen and Flynn, 2004; Rodriguez-Rivera et al, 2011). For example, Tg2576 mice exhibit increased body weight, fasting hyperglycemia and hyperinsulinemia.…”

Section: Introductionmentioning

confidence: 99%

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

Velázquez

Tran

Ishimwe

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are not known, several risk factors have been identified. Among these, type 2 diabetes (T2D), a chronic metabolic disease, is one of the most prevalent risk factors for AD. Insulin resistance, which is associated with T2D, is defined as diminished or absent insulin signaling, and is reflected by peripheral blood hyperglycemia and impaired glucose clearance. In this study, we used complimentary approaches to probe for peripheral insulin resistance, central nervous system (CNS) insulin sensitivity and energy homeostasis in Tg2576 and 3xTg-AD mice, two widely used animal models of AD. We report that CNS insulin signaling abnormalities are evident months before peripheral insulin resistance. Additionally, we find that brain energy metabolism is differentially altered in both mouse models, with the 3xTg-AD mice showing more extensive changes. Collectively, our data suggest that early AD may reflect engagement of different signaling networks that influence CNS metabolism, which in-turn may alter peripheral insulin signaling.

show abstract

“…Many γ‐secretase inhibitors have been developed and are under preclinical and clinical evaluation for therapeutic utility (Imbimbo & Giardina, ; Wolfe, ). Radiolabeled or biotinylated compounds, including compound D and L‐685,458, have been also used as molecular probes for mapping active γ‐secretase sites and activity in vitro and in vivo (Li et al ., ; Yan et al ., ; Patel et al ., ; Goldstein et al ., ; Xiong et al ., ; Frykman et al ., ). In a previous study, γ‐secretase binding sites assayed with [ 3 H]‐compound D were found to be similar in the cerebral cortex in a small group of AD relative to control cases (Patel et al ., ).…”

Section: Introductionmentioning

confidence: 99%

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Liu

Xue

Deng

et al. 2013

Eur J of Neuroscience

View full text Add to dashboard Cite

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD.

show abstract

Ex Vivo Occupancy of γ-Secretase Inhibitors Correlates with Brain β-Amyloid Peptide Reduction in Tg2576 Mice

Cited by 11 publications

References 45 publications

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease

γ‐Secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ

Contact Info

Product

Resources

About