Structural and Chemical Biology of Presenilin Complexes

Johnson, Douglas S.; Li, Yueming; Pettersson, Martin; George-Hyslop, Peter St

doi:10.1101/cshperspect.a024067

Cited by 18 publications

(7 citation statements)

References 152 publications

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“…Since the surprising discovery of sulindac sulphide and two other nonsteroidal anti-inflammatory drugs (NSAIDs) that reduced Aβ42 production from cells ( 15 ), hundreds of compounds have been generated to modulate γ-secretase activity allosterically with the goal to enhance γ-processivity toward the shorter end products, Aβ 38 and 37, an effect similar to that of Y106A, which we observed above. Current GSMs are divided into two broad classes of compounds: the NSAID (acidic) type and the heterocyclic (nonacidic) type ( 16 ). We tested the performance of three acidic GSMs (GSM-1, TC-E 5006, and JNJ-40418677) and two heterocyclic GSMs (E2012 and sGSM-40) ( 17 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

Liu

Lauro

Wolfe

et al. 2021

Journal of Biological Chemistry

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γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides.

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Section: Resultsmentioning

confidence: 99%

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

Liu

Lauro

Wolfe

et al. 2021

Journal of Biological Chemistry

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“…The AβPP is a long, insoluble amyloid fiber and single-pass transmembrane protein ( Chakravarthy et al, 2017 ). Mutations within or flanking the Aβ domain of AβPP are associated with early-onset autosomal dominant forms of FAD ( Johnson et al, 2017 ). In addition, Aβ produced peripherally by various cell types is transported into the brain across the BBB through transcytosis mediated by receptors such as RAGE ( Greenberg et al, 2020 ).…”

Section: Amyloid-βmentioning

confidence: 99%

Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Wang

Chen²,

Han

et al. 2021

Front. Cell. Neurosci.

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Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer’s disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood–brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

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“…Pathogenic mutations in presenilin 1 and 2 genes (PSEN1, PSEN2) also cause familial AD, with PSEN1 mutations being the most common among dominantly inherited FAD kindreds. Presenilin proteins are the catalytic subunits of the gamma-secretase complex required along with beta secretase 1 (BACE1) for Aβ peptide processing and secretion [5]. Sequential C-terminal Aβ cleavage by gamma secretase generates Aβ fragments of differing lengths, with 40 amino acid (Aβ40) and 42 amino acid (Aβ42) being the most common.…”

Section: Genetic Evidencementioning

confidence: 99%

The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation

Castellani

Plascencia-Villa

Perry

2019

Laboratory Investigation

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The identification of amyloid-β precursor protein (APP) pathogenic mutations in familial early onset Alzheimer's disease (AD), along with knowledge that amyloid-β (Aβ) was the principle protein component of senile plaques, led to the establishment of the amyloid cascade hypothesis. Down syndrome substantiated the hypothesis, given an extra copy of the APP gene and invariable AD pathology hallmarks that occur by middle age. An abundance of support for the amyloid cascade hypothesis followed. Prion-like protein misfolding and non-Mendelian transmission of neurotoxicity are among recent areas of investigation. Aβ-targeted clinical trials have been disappointing, with negative results attributed to inadequacies in patient selection, challenges in pharmacology, and incomplete knowledge of the most appropriate target. There is evidence, however, that proof of concept has been achieved, i.e., clearance of Aβ during life, but with no significant changes in cognitive trajectory in AD. Whether the time, effort, and expense of Aβ-targeted therapy will prove valuable will be determined over time, as Aβ-centered clinical trials continue to dominate therapeutic strategies. It seems reasonable to hypothesize that the amyloid cascade is intimately involved in AD, in parallel with disease pathogenesis, but that removal of toxic Aβ is insufficient for an effective disease modification.

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Structural and Chemical Biology of Presenilin Complexes

Cited by 18 publications

References 152 publications

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation

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