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Generation and deposition of A?43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.

ABSTRACT: As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-? peptide (A?) species, which are released from a C-terminal amyloid precursor protein fragment by ?-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the A?42 to A?40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD We now show that the very little A? generated by PS1 L435F consists primarily of A?43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of A?43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found A?43-containing plaques in brains of patients with this mutation. The aberrant generation of A?43 by this particular mutant provides a direct objection against the presenilin hypothesis.

SUBMITTER: Kretner B

PROVIDER: S-EPMC5119496 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.

Kretner Benedikt B Trambauer Johannes J Fukumori Akio A Mielke Janina J Kuhn Peer-Hendrik PH Kremmer Elisabeth E Giese Armin A Lichtenthaler Stefan F SF Haass Christian C Arzberger Thomas T Steiner Harald H

EMBO molecular medicine 20160502 5

As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal amyloid precursor protein fragment by γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major a ...[more]

PMID: 26988102

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Project description:BackgroundIn contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Project description:Fibrillar amyloid-? (A?) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the accumulation of A? in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of A? deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18-60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar A? deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar A? deposition.We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar A? began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3-33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. (18)F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3-40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease.Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.

Dataset Information

Generation and deposition of A?43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.

Publications

Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.

Similar Datasets

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