Intraneuronal Alzheimer Aβ42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

Takahashi, Reisuke H.; Milner, Teresa A.; Li, Feng; Nam, Ellen E.; Edgar, Mark A.; Yamaguchi, Haruyasu; Beal, M. Flint; Xu, Huaxi; Greengard, Paul; Gouras, Gunnar K.

doi:10.1016/s0002-9440(10)64463-x

Cited by 706Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Intraneuronal Alzheimer Aβ42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

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Takahashi, Reisuke H., Milner, Teresa A., Li, Feng, Nam, Ellen E., Edgar, Mark A., Yamaguchi, Haruyasu, Beal, M. Flint, Xu, Huaxi +2 more·2002·The American Journal of Pathology

DOI 10.1016/s0002-9440(10)64463-xPMC PMC1850783

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Abstract

A central question in Alzheimer's disease concerns the mechanism by which beta-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months before the appearance of beta-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal beta-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before beta-amyloid plaque pathology, suggesting that intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's disease.

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Gradual accumulation of amyloid beta begins in the early stages of Alzheimer's disease and initiates synaptic loss, neuroinflammation, neurofibrillary tangle formation, and neuronal dysfunction.
“The gradual accumulation of amyloid-β (Aβ) begins in the early stages of Alzheimer’s disease (AD) and initiates a series of events resulting in synaptic loss, neuroinflammation, the formation of neurofibrillary tangles, and neuronal dysfunction [27, 30, 71].”
From Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease (2023) · cites this paper as [71]
The Abstract (page not supplied) reports that intraneuronal Aβ42 increased with aging and was associated with abnormal synaptic morphology before plaque pathology; it also describes functional decline as Aβ levels rise. It does not establish that Aβ accumulation initiates the claimed sequence of synaptic loss, neuroinflammation, neurofibrillary tangles, and neuronal dysfunction. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Intraneuronal Aβ42 accumulates prominently in the multivesicular body (MVB) of neurites and presynaptic compartments, which precedes the appearance of Aβ in extracellular Aβ plaques.
“Intraneuronal Aβ42 accumulates prominently in the multivesicular body (MVB) of neurites and presynaptic compartments, which precedes the appearance of Aβ in extracellular Aβ plaques [18, 72].”
From Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease (2023) · cites this paper as [72]
Accumulation of intraneuronal Aβ has been observed in the brains of AD, Down's syndrome, and AD mouse models.
“Accumulation of intraneuronal A 𝛃 has been observed in the brains of AD (Gouras et al., 2000; Takahashi et al., 2002; Cataldo et al., 2004; Takahashi et al., 2004), Down's syndrome (DS) (Gouras et al., 2000; Gyure et al., 2001; Busciglio et al., 2002; Mori et al., 2002; Cataldo et al., 2004), and AD mouse models (Takahashi et al., 2002; Oddo et al., 2003; Schmitz et al., 2004), implying potential”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Takahashi et al., 2002
Some AD transgenic mice also display intraneuronal Aβ.
“Some AD transgenic mice also display intraneuronal A 𝛃 (Takahashi et al., 2002; Oddo et al., 2003; Schmitz et al., 2004).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Takahashi et al., 2002
Other APP transgenics display intraneuronal Aβ but do not have significant neuron death.
“Other APP transgenics also display intraneuronal A 𝛃 but do not have significant neuron death (Takahashi et al., 2002; Oddo et al., 2003).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Takahashi et al., 2002

Aβ accumulation within neurites may contribute to degeneration and deposit formation.
“Plaques are frequently seen in somapoor regions of neuropil and white matter (e.g., stratum oriens andstratumradiatumofthehippocampus,molecularlayer of the dentate gyrus, and fimbria) (Fig. 4 D ), consistent with the hypothesis that A 𝛃 accumulation within neurites may contribute to degeneration and deposit formation (Takahashi et al., 2002).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Takahashi et al., 2002
Early increases in intracellular amyloid-β levels have been observed in vulnerable neurons of Alzheimer's disease human patients and animal models, preceding the appearance of amyloid-β plaques.
“Apart from extracellular deposition, early increases in intracellular Aβ levels have been observed in vulnerable neurons of AD human patients [41, 78] and animal models [22, 87, 110], preceding the appearance of Aβ plaques.”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [110]
Intraneuronal amyloid-β accumulation in specific Alzheimer's disease-vulnerable neurons precedes the formation of extracellular amyloid-β plaques both in Alzheimer's disease patients and mouse models.
“Additionally, it has been shown that intraneuronal Aβ accumulation in specific AD-vulnerable neurons precedes the formation of extracellular Aβ plaques both in AD patients [41, 78] and mouse models [22, 87, 110].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [110]
Aβ42 labeling is absent in neurons of APP knockout mouse brains.
“Aβ42 labeling was shown to be absent in neurons of APP knockout mouse brains”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
Neurons in normal wild-type mouse, rat and human brains show localization of Aβ42 primarily associated with endosomal organelles, often late endosomal multivesicular bodies (MVBs).
“neurons in normal wild-type mouse, rat and human brains showed localization of Aβ42 primarily associated with endosomal organelles, often identifiable on electron micrographs as late endosomal multivesicular bodies (MVBs; [188]).”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
APP has a different subcellular localization (primarily Golgi apparatus) compared to Aβ42 (primarily endosomes).
“dual-immuno-EM further indicated that APP has a different subcellular localization (primarily Golgi apparatus) compared to Aβ42 (primarily endosomes).”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
Emerging data, such as FAD mutations and the direct association of intraneuronal Aβ42 with subcellular pathology, cell death, and behavioral and physiological abnormalities prior to plaques in AD transgenic mouse models, provide increasing evidence for the importance of intraneuronal Aβ.
“Emerging data, such as FAD mutations noted above, and the direct association of intraneuronal Aβ42 with subcellular pathology [187, 188], cell death [23, 167], and behavioral and physiological abnormalities, even prior to plaques, in AD transgenic mouse models [140], are providing increasing evidence for the importance of intraneuronal Aβ.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
The most marked accumulation of intraneuronal Aβ42 occurs in distal neurites and synaptic compartments as determined by immuno-EM, which cannot be visualized effectively by light or standard immuno-fluorescence microscopy.
“the most marked accumulation of intraneuronal Aβ42 occurs in distal neurites and synaptic compartments as determined by immuno-EM [188] that cannot be visualized effectively by light or standard immuno-fluorescence microscopy.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
Immuno-EM images of Aβ42-accumulating dystrophic neurites lacking normal microtubule tracks argue against active secretion of aggregating Aβ42 from neurites prior to plasma membrane dissolution.
“Immuno-EM images of completely abnormal Aβ42 accumulating dystrophic neurites [187, 188], lacking the normal microtubule tracks required for organelle trafficking, secretion and exocytosis, argue against the active secretion of aggregating Aβ42 from neuritis prior to the dissolution of the plasma membrane [95].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
More prominent increases in Aβ42 accumulation were observed in distal dendrites compared to axons.
“Overall, more prominent increases in Aβ42 accumulation were observed in distal dendrites compared to axons [188], although there are anatomical differences, and it remains possible that either axons or dendrites are the initial site of intraneuronal Aβ pathology.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]
Pathological accumulation is most prominent in distal neurites and synapses of AD transgenic mice and provided the first direct association between Aβ and synapse pathologies in the brain.
“That this pathological accumulation is most prominent in distal neurites and synapses of AD transgenic mice provided the first direct association between Aβ and synapse pathologies in the brain [188].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [188]

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Authors: Takahashi, R. H., Milner, T. A., Li, F., Nam, E. E., Edgar, M. A., Yamaguchi, H., Beal, M. F., Xu, H., Greengard, P., & Gouras, G. K.
Affiliations: Cornell University (US)
Gunma University (JP)
Rockefeller University (US)
Corresponding author: Gouras, Gunnar K.
ORCID: Takahashi, Reisuke H.
Milner, Teresa A.
Li, Feng
Edgar, Mark A.
Beal, M. Flint
Xu, Huaxi
Greengard, Paul
Gouras, Gunnar K.
Venue: The American Journal of Pathology
Publisher: Elsevier BV
Published: 2002-11
Volume: 161
Issue: 5
Pages: 1869-1879
ISSN: 0002-9440 (ISSN-L)
DOI: 10.1016/s0002-9440(10)64463-x
PMC: PMC1850783
OpenAlex: W2030508474
Cited by: 706
References: 70
Citations by year: 2026: 13 · 2025: 22 · 2024: 19 · 2023: 21 · 2022: 30 · 2021: 31 · 2020: 24 · 2019: 27 · 2018: 32 · 2017: 32 · 2016: 33 · 2015: 36 · 2014: 30 · 2013: 34 · 2012: 46
FWCI: 14.99
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: American Journal Of Pathology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Alzheimer's Association (NS02037, AG09464)
American Academy of Neurology
National Institutes of Health (2k08ns002037-04, HL18974)
National Institute on Aging (AG09464, P01AG009464)
National Heart, Lung, and Blood Institute (HL-18974, P01HL018974)
National Institute of Neurological Disorders and Stroke (NS02037)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, amyloid-beta 42, multivesicular bodies, synaptic pathology, postsynaptic compartment, subcellular localization, transgenic mouse model, aging, immunoelectron microscopy
MeSH terms: Aging, Alzheimer Disease, Animals, Brain, Humans, Mice, Transgenic, Middle Aged, Neurons, Peptide Fragments, Synapses, Amyloid beta-Peptides, Microscopy, Immunoelectron, Amyloid beta-Protein Precursor, Mice, Knockout, Cytoplasmic Vesicles, Mice, Rats

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Intraneuronal Alzheimer Aβ42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology

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