Alzheimer's disease

Scheltens, Philip; Strooper, Bart De; Kivipelto, Miia; Holstege, Henne; Chételat, Gaël; Teunissen, Charlotte E.; Cummings, Jeffrey L.; Flier, Wiesje M. van der

doi:10.1016/s0140-6736(20)32205-4

Cited by 2,501 publications

(1,789 citation statements)

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“…APP consists of a cytoplasmic C-terminus followed by a single transmembrane domain and an extracellular glycosylated N-terminus. Human APP can be processed through two different routes, defined as non-amyloidogenic and amyloidogenic pathways [187]. In the non-amyloidogenic processing, the enzyme α-secretase cleaves the extracellular domain, producing a short soluble N-terminal fragment and leaving a membrane-bound 83 kDa fragment [187][188][189].…”

Section: The Curious Case Of Aβmentioning

confidence: 99%

“…Human APP can be processed through two different routes, defined as non-amyloidogenic and amyloidogenic pathways [187]. In the non-amyloidogenic processing, the enzyme α-secretase cleaves the extracellular domain, producing a short soluble N-terminal fragment and leaving a membrane-bound 83 kDa fragment [187][188][189]. This cleavage is regulated by electrical activity and upon muscarinic acetylcholine receptor activation, suggesting a role in synaptic activity [189].…”

Section: The Curious Case Of Aβmentioning

confidence: 99%

“…This cleavage is regulated by electrical activity and upon muscarinic acetylcholine receptor activation, suggesting a role in synaptic activity [189]. The membrane-bound fragment is further processed by the γ-secretase complex, consisting of four different proteins termed presenilin 1 and 2, nicastrin and anterior pharynx defective-2 [187,190]. Presenilins, the active components of the γ-secretase complex, catalyze a proteolytic cleavage on aspartate residues within the hydrophobic 83 kDa domain, liberating a short fragment (3 kDa) and an intracellular domain.…”

Section: The Curious Case Of Aβmentioning

confidence: 99%

“…In the amyloidogenic pathway, APP is first cleaved by β-secretase, which produces a 99 kDa C-terminal moiety. This region is further processed heterogeneously by γ-secretase, resulting in the production of Aβ peptides of sizes ranging from 37 to 49 amino acids [187,191,192].…”

Section: The Curious Case Of Aβmentioning

confidence: 99%

“…Likewise, Aβ fragments of various sizes were shown by NMR to display very different conformational states (see ref. [187] for an in-depth review of the structures Aβ fragments may adopt in solution). The two major forms of Aβ found in pathology are Aβ 1-40 and Aβ 1-42 [195].…”

Section: The Curious Case Of Aβmentioning

confidence: 99%

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Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Candelise

Scaricamazza

Salvatori

et al. 2021

IJMS

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Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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Section: The Curious Case Of Aβmentioning

confidence: 99%

Section: The Curious Case Of Aβmentioning

confidence: 99%

Section: The Curious Case Of Aβmentioning

confidence: 99%

Section: The Curious Case Of Aβmentioning

confidence: 99%

Section: The Curious Case Of Aβmentioning

confidence: 99%

See 3 more Smart Citations

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Candelise

Scaricamazza

Salvatori

et al. 2021

IJMS

View full text Add to dashboard Cite

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Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

et al. 2021

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IMPORTANCE Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.OBJECTIVE To examine the prognostic accuracy of baseline fluorine 18 ( 18 F)-flortaucipir and [ 18 F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. DESIGN, SETTING, AND PARTICIPANTS This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). EXPOSURES [ 18 F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18 F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. MAIN OUTCOMES AND MEASURES Baseline [ 18 F]flortaucipir/[ 18 F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. RESULTS Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18 F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2 , 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R 2 , 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R 2 , 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [ 18 F]RO948 PET cohort. MRI mediated the association between [ 18 F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, −17.5% to 39.0%]; P = .71). Age (t = −2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [ 18 F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau...

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