Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses
Willén, Katarina LU ; Sroka, Agnieszka ; Takahashi, Reisuke H. and Gouras, Gunnar K. LU
(2017)
In Journal of Alzheimer's Disease
60(2).
p.511-524
- Abstract
Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to... (More)
Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.
(Less)
- author
- Willén, Katarina
LU
; Sroka, Agnieszka
; Takahashi, Reisuke H.
and Gouras, Gunnar K.
LU
- organization
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer's disease, amyloid-beta, gamma-secretase, synapse
- in
- Journal of Alzheimer's Disease
- volume
- 60
- issue
- 2
- pages
- 14 pages
- publisher
- IOS Press
- external identifiers
-
- scopus:85029611149
- pmid:28869466
- pmid:28869466
- wos:000411203800015
- ISSN
- 1387-2877
- DOI
- 10.3233/JAD-170262
- language
- English
- LU publication?
- yes
- id
- 63fb2207-1f55-461e-9efc-f62bdb9f25de
- date added to LUP
- 2017-09-28 08:54:50
- date last changed
- 2024-03-31 17:26:02
@article{63fb2207-1f55-461e-9efc-f62bdb9f25de,
abstract = {{<p>Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ<sub>42</sub> accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ-secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging.</p>}},
author = {{Willén, Katarina and Sroka, Agnieszka and Takahashi, Reisuke H. and Gouras, Gunnar K.}},
issn = {{1387-2877}},
keywords = {{Alzheimer's disease; amyloid-beta; gamma-secretase; synapse}},
language = {{eng}},
number = {{2}},
pages = {{511--524}},
publisher = {{IOS Press}},
series = {{Journal of Alzheimer's Disease}},
title = {{Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses}},
url = {{http://dx.doi.org/10.3233/JAD-170262}},
doi = {{10.3233/JAD-170262}},
volume = {{60}},
year = {{2017}},
}