Spastic paraplegia preceding PSEN1-related familial Alzheimer's disease

Abstract

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 manifesting 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 history of cognitive decline.

Keywords: Alzheimer's disease; HSP; PSEN1; dementia; hereditary spastic paraplegia; presenilin; spastic gait; spastic paraparesis; spastic paraplegia.

FIGURE 1

Genetic and protein analysis for the PSEN1 mutation–associated spastic paraplegia. A, Pedigree of the family reported in this study. B, Sanger sequencing confirmation of the proband highlighting the c.871A > C (p.Thr291Pro) mutation. C, Localization of PSEN1 mutations associated with spastic paraparesis as presenting phenotype. PSEN1 protein has nine transmembrane domains. Pathogenic substitutes in the p.Thr291Pro and other reported mutations are shown

FIGURE 2

AD‐linked p.Thr291Pro PSEN1 destabilizes γ‐secretase‐APPc99/Aβ interactions resulting in generation of longer Aβ peptides. A, Representative SDS‐PAGE/western blot analysis of CHAPSO‐solubilized membranes from dKO PS1/PS2 mouse embryonic fibroblasts (MEFs) stably expressing wild‐type (WT) or mutant p.Thr291Pro hPS1. The presence of mature, glycosylated NCT, C‐terminal fragment of the endoproteolyzed PS1 and PEN2 (compared to dKO PS1/PS2 cells) indicates that p.Thr291Pro hPS1 reconstitutes active γ‐secretase complexes. Arrowheads indicate the position of molecular weight markers. B, Aβ profiles generated by solubilized membranes prepared from stable MEF PS1/2 dKO cell lines expressing WT or p.Thr291Pro hPS1 γ‐secretase in in vitro activity assays with purified APPC99‐3xFLAG. Increase in the production of Aβ42 at the expense of the shorter Aβ38 and Aβ40 indicates pathogenic impairment of γ‐secretase processivity of APPC99 by the AD‐linked p.Thr291Pro hPS1 mutation. N = 3 ± SD. C, In vitro thermoactivity data confirm that mutant p.Thr291Pro hPS1 destabilizes γ‐secretase‐APPC99/Aβ interactions, when compared to the WT complex, at the level of total activity (AICD generation) as well as Aβ peptide production, inducing premature dissociation of long Aβ peptides. N ≥ 3 ± SD

FIGURE 3

Neuropathological study in individual II‐1 from this study (c.871A ≥ C, p.Thr291Pro). A, Several vessels with thickened vessels showing congophilia (black arrows; Congo Red staining). B, Higher magnification of A with congophilia of blood vessels (B) and after polarization of the same area showing typical apple‐green color (white arrow in C). D, Beta‐A4‐amyloid immunohistochemistry confirms amyloid deposition within the vessel walls (black arrows) and in addition several diffuse cortical plaques (white arrows), with the characteristic morphology of cotton‐wool plaques