Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro

Meghan K. Cash; Kenneth Rockwood; John D. Fisk; Sultan Darvesh

doi:10.1016/j.neurobiolaging.2021.02.025

Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro

Meghan K. Cash, Kenneth Rockwood, John D. Fisk, Sultan Darvesh

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with β-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for β-amyloid, tau, α-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but α-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with α-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with β-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.

Original language	English
Pages (from-to)	31-41
Number of pages	11
Journal	Neurobiology of Aging
Volume	103
DOIs	https://doi.org/10.1016/j.neurobiolaging.2021.02.025
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
2. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease.

Funding Information:
We would also like to thank Professor Earl Martin for his generous input and assistance while preparing the manuscript. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease.

Publisher Copyright:
© 2021

ASJC Scopus Subject Areas

General Neuroscience
Ageing
Developmental Biology
Clinical Neurology
Geriatrics and Gerontology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.neurobiolaging.2021.02.025

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title = "Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro",

abstract = "In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with β-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for β-amyloid, tau, α-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but α-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with α-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with β-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.",

author = "Cash, {Meghan K.} and Kenneth Rockwood and Fisk, {John D.} and Sultan Darvesh",

note = "Funding Information: 2. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease. Funding Information: We would also like to thank Professor Earl Martin for his generous input and assistance while preparing the manuscript. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease. Publisher Copyright: {\textcopyright} 2021",

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AU - Darvesh, Sultan

N1 - Funding Information: 2. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease. Funding Information: We would also like to thank Professor Earl Martin for his generous input and assistance while preparing the manuscript. This work was supported in part by the Canadian Institutes of Health Research (MOP-82798, RNS-117795, MOP-119343, PJT- 153319), Nova Scotia Health Research Foundation (MED-MAT-2011-7512), Faculty and Department of Medicine of Dalhousie University, Innovacorp, Dalhousie Medical Research Foundation (Adopt-a-Researcher Program – Ms. Sadie MacLeod and Mr. Jim Spatz and the Durland Breakthrough Fund), and the Dalhousie Medical Research Foundation Irene MacDonald Sobey Endowed Chair in Curative Approaches to Alzheimer's Disease. Publisher Copyright: © 2021

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N2 - In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with β-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for β-amyloid, tau, α-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but α-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with α-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with β-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.

AB - In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with β-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for β-amyloid, tau, α-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but α-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with α-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with β-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.

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ER -

Clinicopathological correlations and cholinesterase expression in early-onset familial Alzheimer's disease with the presenilin 1 mutation, Leu235Pro

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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