Journal Article

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques

Hashizume, Yoshio, Miyazaki, Tatsuhiko, KImura, Naoto, Yamamoto, Takayuki, Kamada, Kazuo, Hori, Akira, Mimuro, Maya, Wake, Akito, Sato, Naoyuki, Miki, Tetsuro, Yamagata, Hidehisa D., Akatsu, Hiroyasu, Watanabe, Ichiro, Yoshida, Mari, Fukuoka, Tomoya

2024

Overview

Background The mutations in the presenilin 1 gene ( PSEN1 ) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Method Using the proband’s samples, we performed genetic analysis of the PSEN1 , APP , MAPT , and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1 . Results The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Conclusion Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Alzheimer's disease / Amyloid beta-Peptides - genetics / Amyloid beta-Peptides - metabolism / Animals / Apolipoprotein E / Atrophy / Axons / Biochemical analysis / Blood flow / Brain - metabolism / Brain - pathology / Cerebral amyloid angiopathy / Cerebral blood flow / Chlorocebus aethiops / Dementia - genetics / Dementia - pathology / Dementia disorders / Electron microscopy / Environmental factors / Female / Fibrils / Genetic analysis / Humans / Lewy bodies / Male / Medicine / Medicine & Public Health / Memory / Middle Aged / Mutation / Neurodegeneration / Neurodegenerative diseases / Neurology / Neuroradiology / Neurosurgery / Original Article / Phenotype / Phenotypes / Plaque, Amyloid - genetics / Plaque, Amyloid - pathology / Plaques / Presenilin 1 / Presenilin-1 - genetics / Psychiatry / Senile plaques / Substantia alba / tau Proteins - genetics / tau Proteins - metabolism / β-Amyloid