Τίτλος:
Spastic paraplegia preceding psen1-related familial alzheimer’s disease
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Introduction: We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer’s disease (AD). Methods: We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP-related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ-secretase. Results: We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ-secretase reconstitution, it destabilizes γ-secretase-amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases mani-festing initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid-ring arteries, and severe CAA. Discussion: We show that pure SP can precede dementia onset in PSEN1-related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP-related genes, particularly when associated with a family his-tory of cognitive decline. © 2021 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association.
Συγγραφείς:
Chelban, V.
Breza, M.
Szaruga, M.
Vandrovcova, J.
Murphy, D.
Lee, C.-J.
Alikhwan, S.
Bourinaris, T.
Vavougios, G.
Ilyas, M.
Halim, S.A.
Al-Harrasi, A.
Kartanou, C.
Ronald, C.
Blumcke, I.
Alexoudi, A.
Gatzonis, S.
Stefanis, L.
Karadima, G.
Wood, N.W.
Chávez-Gutiérrez, L.
Hardy, J.
Houlden, H.
Koutsis, G.
Περιοδικό:
Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
Εκδότης:
John Wiley and Sons Inc
Λέξεις-κλειδιά:
amyloid beta protein[1-42]; presenilin 1; secretase, adult; Alzheimer disease; animal cell; Article; brain biopsy; cognitive defect; cohort analysis; dementia; enzyme assay; familial disease; gene mutation; gene set enrichment analysis; hereditary motor sensory neuropathy; human; immunocytochemistry; major clinical study; male; Montreal cognitive assessment; mouse; neurologic disease assessment; neuropathology; nonhuman; nuclear magnetic resonance imaging; pedigree analysis; phenotype; retrospective study; spastic paraplegia rating scale; thermoactivity assay; Western blotting; whole exome sequencing
