Dataset Information

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

ABSTRACT:

Background

Alzheimer's disease (AD) is the second-most frequent cause underlying corticobasal syndrome (CBS). However, a reliable diagnosis using clinical, neuropsychological, or neuroimaging approaches has not yet been achieved.

Methods

Clinical, neuropsychological, imaging, and neuropathology studies were undertaken in a large Spanish family with early-onset familial AD (EOFAD) carrying a Met233Leu mutation linked to presenilin-1 gene (PSEN-1).

Results

Two of three examined members of this family presented with the usual amnestic pattern. At the age of 47 years, a third family member, in whom pathology was later confirmed, developed prominent CBS combined with severe neuropsychiatric and behavioral disturbances resembling those often found in EOFAD.

Conclusion

Although CBS in EOFAD appears to be rare, demonstration of a linkage to PSEN-1 gene mutations may permit in vivo diagnosis.

SUBMITTER: Navarro E

PROVIDER: S-EPMC6353493 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

Navarro Eloisa E De Andrés Clara C Guerrero Carmen C Giménez-Roldán Santiago S

Movement disorders clinical practice 20150725 4

<h4>Background</h4>Alzheimer's disease (AD) is the second-most frequent cause underlying corticobasal syndrome (CBS). However, a reliable diagnosis using clinical, neuropsychological, or neuroimaging approaches has not yet been achieved.<h4>Methods</h4>Clinical, neuropsychological, imaging, and neuropathology studies were undertaken in a large Spanish family with early-onset familial AD (EOFAD) carrying a Met233Leu mutation linked to presenilin-1 gene (PSEN-1).<h4>Results</h4>Two of three examin ...[more]

PMID: 30838239

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Project description:ObjectivesAlzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in γ-secretase complex, the mutations of PS1 gene cause the interference of γ-secretase activity and lead to the increased Aβ42 secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons.Materials and methodsMononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC-derived neurons using Mito-tracker.ResultsWe observed that both extracellular and intracellular Aβ levels were dramatically increased in the PS1-S170F iPSC-derived neurons, compared with the control iPSC-derived neurons. Furthermore, PS1-S170F iPSC-derived neurons showed high expression levels of p-Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1-S170F iPSC-derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion-related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission-related protein DRP1 (dynamin-related protein 1) in the PS1-S170F iPSC-derived neurons. We further observed the defects of autophagy-related clearance in the PS1-S170F iPSC-derived neurons. Finally, we demonstrated the levels of Aβ and p-Tau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor.ConclusionsTaken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.

Project description:Presenilin-2 (PSEN2) mutation Thr421Met was identified from a 57-years old patient with early onset Alzheimer's disease (EOAD) for the first time in Korea. Previously, this mutation was discovered in an EOAD patient in Japan without a change on amyloid production from the cellular study. Both Korean and Japanese patients developed the disease in their 50s. Memory loss was prominent in both cases, but no additional clinical information was available on the Japanese patient. Magnetic resonance imaging (MRI) images of the Korean patient revealed asymmetric atrophies in both temporo-parietal lobes. In addition, amyloid positron emission tomography (PET) also revealed amyloid deposits in the gray matter of the temporo-parietal lobes asymmetrically. PSEN2 Thr421 was conserved among a majority of vertebrates (such as zebras, elephants, and giant pandas); hence, Thr421 could play an important role in its functions and any mutations could cause detrimental ramifications in its interactions. Interestingly, PSEN2 Thr421 could have homology with PSEN1 Thr440, as PSEN1 T440del mutations were reported from patients with AD or dementia with Lewy bodies. Hence, the changed amino acid from threonine to methionine of PSEN2 Thr421 could cause significant structural alterations in causing local protein dynamics, leading to its pathogenicity in EOAD. Lastly, PSEN2 Thr421Met may interact with other mutations in neurodegenerative disease related genes, which were found in the proband patient, such as ATP binding cassette subfamily A member 7 (ABCA7), Notch Receptor 3 (NOTCH3), or Leucine-rich repeat kinase 2 (LRRK2). These interactions of pathway networks among PSEN2 and other disease risk factors could be responsible for the disease phenotype through other pathways. For example, PSEN2 and ABCA7 may impact amyloid processing and reduce amyloid clearance. Interaction between PSEN2 and NOTCH3 variants may be associated with abnormal NOTCH signaling and a lower degree of neuroprotection. Along with LRRK2 variants, PSEN2 Thr421Met may impact neurodegeneration through Wnt related pathways. In the future, cellular studies of more than one mutation by CRISPR-Cas9 method along with biomarker profiles could be helpful to understand the complicated pathways.

Dataset Information

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

Background

Methods

Results

Conclusion

Publications

Corticobasal Syndrome in a Family with Early-Onset Alzheimer's Disease Linked to a Presenilin-1 Gene Mutation.

Similar Datasets

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