Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process

Strooper, Bart De

doi:10.1152/physrev.00023.2009

Cited by 387 publications

(334 citation statements)

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“…Yield: 83%. 1 Ethyl-3-(6-(4-chlorophenylsulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoate (4). A solution of (E)-ethyl-3-(6-(benzylamino)-5,6,7,8-tetrahydronaphthalen-1-yl)acrylate (120 mg, 0.36 mmol) in ethyl alcohol (10 mL) was added with hydrochloric acid (1.0 equiv, 1 N solution in water) followed by Pd on C (10 wt %; 50% wet).…”

Section: ■ Methodsmentioning

confidence: 99%

“…Aliquots (50 μL) of mouse brain homogenate (1:2 w/v in 10 mM NH 4 OAc, pH 5.7) or plasma were extracted with acetonitrile (1:5 v/v), centrifuged, and the supernatant removed for LC-MS/MS analysis (Waters Acquity UPLC-TQD, Milford, MA). Analytes were separated by reversed phase liquid chromatography using a water/acetonitrile/0.1% formic acid gradient and detected in the positive ion mode.…”

Section: ■ Methodsmentioning

confidence: 99%

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Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Soper

Sugiyama

Herbst-Robinson

et al. 2012

ACS Chem. Neurosci.

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A hallmark pathological feature of the Alzheimer's disease (AD) brain is the presence of senile plaques, which comprise amyloid β (Aβ) peptides that are derived from the amyloid precursor protein (APP). The plaque-containing AD brain is thought to be under oxidative stress, as evidenced by increased lipid oxidation products that include isoprostane-F2αIII (iPF2αIII). IPF2αIII can bind to and activate the thromboxane A2-prostanoid (TP) receptor, and TP receptor activation causes increased Aβ production through enhancement of APP mRNA stability. Moreover, TP receptor antagonists have been shown to block iPF2αIII-induced increases of Aβ secretion. Thus, the TP receptor may be a potential drug target for AD therapy. However, here we show that existing TP receptor antagonists have poor blood-brain barrier (BBB) permeability, likely due to the presence of a carboxylic acid moiety that is believed to be important for receptor interaction, but which may hamper passive diffusion across the BBB. We now report selected analogues of a known tetrahydronaphthalene TP receptor antagonist, wherein the carboxylic acid moiety has been replaced by heterocyclic bioisosteres. These heterocyclic analogues retained relatively high affinity for the mouse and human TP receptors, and, unlike the parent carboxylic acid compound, several examples freely diffused across the BBB into the brain upon administration to mice. These results reveal that brain-penetrant tetrahydronaphthalene TP receptor antagonists can be developed by substituting the carboxylic acid moiety with a suitable nonacidic bioisostere. Compounds of this type hold promise as potential lead structures to develop drug candidates for the treatment of AD. KEYWORDS: Alzheimer's disease, amyloid precursor protein, antagonist, blood-brain barrier, plaques, thromboxane receptor A lzheimer's disease (AD) is the most common cause of dementia in elderly populations, affecting approximately 10% of individuals over age 65. 1,2 The AD brain is characterized by overt neurodegeneration 3 and the presence of senile plaques comprising insoluble fibrils of Aβ peptides which are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP). 4 A second pathological hallmark of the AD brain is the occurrence of intracellular inclusions composed of hyperphosphorylated tau proteins. 5,6 Familial forms of AD can be caused by mutations in APP that result in increased proteolytic generation of amyloidogenic Aβ peptides, as well as by mutations in the presenilin proteins that are required for the proteolytic processing of APP to yield Aβ. 7−10 These genetic data provide compelling support for the "amyloid" hypothesis, which postulates that it is the production of Aβ that drives disease pathogenesis in AD. Accordingly, there is significant interest in identifying therapeutic strategies that will lead to decreased Aβ production, and there are ongoing efforts to identify inhibitors of the enzymes that generate Aβ. 11,12 A consequence of Aβ plaque deposition in the AD ...

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Section: ■ Methodsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Brain-Penetrant Tetrahydronaphthalene Thromboxane A2-Prostanoid (TP) Receptor Antagonists as Prototype Therapeutics for Alzheimer’s Disease

Soper

Sugiyama

Herbst-Robinson

et al. 2012

ACS Chem. Neurosci.

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“…While the present study only focused on Ab40 and Ab42, it should be noted that there are many additional Ab isoforms with various amino-and carboxy terminal lengths. In addition, there are Ab amino-acid sequence differences associated with familial forms of cerebral b-amyloidosis [5,29]. The physiological relevance of Ab 'strains' and whether they can be linked to phenotypic variability of AD and/or cerebral b-amyloidosis, as reported for prion strains in prionoses [18][19][20], remains to be shown.…”

Section: Transmission Of Ab Morphotypesmentioning

confidence: 99%

Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

et al. 2013

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The polymorphic b-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral b-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop b-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Ab40/Ab42 peptide ratio. To determine the nature of such b-amyloid morphotypes, b-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced b-amyloid deposition with the morphological, conformational, and Ab40/Ab42 ratio characteristics of b-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of b-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced b-amyloid deposits, although less prominent, and the induced deposits were similar to the b-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Ab in APP transgenic mice can be maintained by seeded conversion.

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“…Confusing matters, however, were the subsequent findings of obligatory partners to PS and γ-secretase activity. γ-Secretase activity requires association of PS with three other subunitsnamely, nicastrin (NCT), anterior pharynx defective 1 (APH-1), and presenilin enhancer (PEN2), to form the catalytically active γ-secretase complex (6). In yeast, ectopic expression indicated that these four subunits are required and sufficient for function, and they appear to exist in a 1:1:1:1 stoichiometry (7,8).…”

mentioning

confidence: 99%

“…Ever since the FAD-linked PS1 mutations have been identified, most if not all of the mutations that have been analyzed show two consistently perturbed phenotypes: slight to significant reduction in γ-secretase activity and an increase in the ratio of Aβ42/Aβ40 peptides (6). It has been known for some time that Aβ peptides are heterogenous.…”

mentioning

confidence: 99%