Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation
Abstract
Most cases of familial presenile Alzheimer's disease are caused by mutations in the presenilin-1 (PSEN-1) gene, most of these mutations being missense mutations. A mutation in the splice donor site of intron 4 of PSEN-1 has been described recently which results in aberrant splicing of PSEN-1 mRNA, causing insertion of an additional amino acid, Thr113-114ins, into the protein. We studied the neuropathology of four cases bearing this mutation in an attempt to clarify the pathology of this hereditary form of Alzheimer's disease and to determine whether it differs from other familial forms of the disease. The disease presented as a progressive cognitive decline, myoclonus and seizures developing later in the disease, a feature common to PSEN-1-linked Alzheimer's disease. The course of the disease was relatively rapid, death occurring approximately 6 years after onset. Pathology in the intron 4 cases demonstrated a severe Alzheimer's disease pathology with abundant deposition of ss-amyloid (Ass) 1-42 senile plaques and the formation of neurofibrillary tangles. Amyloid angiopathy was present in these cases and was readily demonstrated by Ass 1-40 staining, particularly in the cerebellum. Cases with the intron 4 mutation appear clinically and pathologically similar to other cases of early-onset Alzheimer's disease bearing PSEN-1 mutations.
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Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA, disrupted meningeal, subpial, and cortical arterioles, degeneration of pericytes and SMCs, cerebral perivascular amyloid deposits, and diminished FDG transport across the BBB in an early asymptomatic stage.
“Human PSEN1 mutation carriers have notable BBB breakdown and cerebrovascular dysfunction including cerebellar amyloid angiopathy and CAA (143, 183, 274, 280, 354, 389, 440, 500, 544, 573, 639, 668); disrupted meningeal, subpial, and cortical arterioles (274, 389, 440); degeneration of pericytes and SMCs (573); cerebral perivascular amyloid deposits (25, 274, 289, 354, 573, 668); and diminished FDG”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [544]
Cerebrovascular pathology with BBB breakdown was shown by neuropathological studies in patients with specific PSEN1 mutations including T113-114 insertion, P117L, M139V, M146V, L153V, H163R, E184D, G209V, A260V, C260T, E280A, L282V, C285T, L420R, and Δe9 deletion.
“Particularly, cerebrovascular pathology with BBB breakdown was shown by neuropathological studies in patients with PSEN1 T113-114 insertion (544), P117L (573, 639), M139V (183, 389), M146V (389), L153V (289), H163R (280), E184D (668), G209V (389), A260V (389), C260T (274), E280A (354), L282V (143), C285T (274), and L420R (440) missense mutations, and 𝚫 e9 deletion (280).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [544]
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Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
PART, a distinct tauopathy, different from classical sporadic Alzheimer disease.
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- Authors
- Singleton, A. B.
- Affiliations
- Newcastle upon Tyne Hospital (GB)
- Corresponding author
- Singleton, A. B.
- ORCID
- Singleton, A. B.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-12-01
- Volume
- 123
- Issue
- 12
- Pages
- 2467-2474
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2161584848
- Cited by
- 36
- References
- 3
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 1 · 2018: 4 · 2017: 1 · 2015: 2 · 2012: 1
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- early-onset Alzheimer's disease, presenilin 1, familial Alzheimer's disease, neuropathology, neurofibrillary tangles, amyloid angiopathy, myoclonus, seizures, cerebellum
- MeSH terms
- Adult, Alzheimer Disease, Cognition Disorders, Diagnosis, Differential, DNA Mutational Analysis, Electroencephalography, England, Female, Humans, Introns, Creutzfeldt-Jakob Syndrome, Membrane Proteins, Mutation, Myoclonus, Pedigree, Seizures, Fatal Outcome, Disease Progression, Presenilin-1
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