Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer’s Disease

Kobro‐Flatmoen, Asgeir; Hormann, Thea Meier; Gouras, Gunnar K.

doi:10.3233/jad-230349

Cited by 6 publications

(2 citation statements)

References 49 publications

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“…In healthy Wistar rats, a low level of intracellular A β 42 is found in neurons throughout the brain at all ages. The highest levels are found in ECLII neurons, in particular in neurons located in the superficial part of this layer, which is the part that contains the Re + ECLII neurons, and in hippocampal neurons at the CA1/subiculum border [38]. This suggests that the baseline production rate of A β is higher in Re + ECLII neurons than in almost all other cortical neurons.…”

Section: Resultsmentioning

confidence: 99%

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Kobro-Flatmoen,

Omholt

2023

Preprint

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It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid-β(Aβ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric Aβin the onset of AD. If reelin functions as a sink for intracellular Aβand if the binding to reelin makes Aβphysiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric Aβ. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of Aβthan neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of Aβin ECLII neurons may in a senescent Aβ-inducing physiology predispose these neurons to initiate AD development.Author summaryAmyloid-βis a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-βand reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid-β, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-β. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-βproduction capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Kobro-Flatmoen,

Omholt

2023

Preprint

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“…Intracellular Aβ accumulation has been reported in endosomes and multivesicular bodies in transgenic rodent models and human brains before extracellular deposition [87][88][89][90][91][92][93].…”

Section: Aβ Plaques Develop Intracellularly Before Cell Deathmentioning

confidence: 99%

A Combination of Heavy Metals and Intracellular Pathway Modulators Induces Alzheimer Disease-like Pathologies in Organotypic Brain Slices

Korde,

Humpel

2024

Biomolecules

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. The present study aims to establish a cost-effective and rapid method to model the two primary pathologies in organotypic brain slices. Coronal hippocampal brain slices (150 µm) were generated from postnatal (day 8–10) C57BL6 wild-type mice and cultured for 9 weeks. Collagen hydrogels containing either an empty load or a mixture of human Aβ42 and P301S aggregated tau were applied to the slices. The media was further supplemented with various intracellular pathway modulators or heavy metals to augment the appearance of Aβ plaques and tau NFTs, as assessed by immunohistochemistry. Immunoreactivity for Aβ and tau was significantly increased in the ventral areas in slices with a mixture of human Aβ42 and P301S aggregated tau compared to slices with empty hydrogels. Aβ plaque- and tau NFT-like pathologies could be induced independently in slices. Heavy metals (aluminum, lead, cadmium) potently augmented Aβ plaque-like pathology, which developed intracellularly prior to cell death. Intracellular pathway modulators (scopolamine, wortmannin, MHY1485) significantly boosted tau NFT-like pathologies. A combination of nanomolar concentrations of scopolamine, wortmannin, MHY1485, lead, and cadmium in the media strongly increased Aβ plaque- and tau NFT-like immunoreactivity in ventral areas compared to the slices with non-supplemented media. The results highlight that we could harness the potential of the collagen hydrogel-based spreading of human Aβ42 and P301S aggregated tau, along with pharmacological manipulation, to produce pathologies relevant to AD. The results offer a novel ex vivo organotypic slice model to investigate AD pathologies with potential applications for screening drugs or therapies in the future.

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Myelinated Glial Cells: Their Proposed Role in Waste Clearance and Neurodegeneration in Arachnid and Human Brain

Fabian‐Fine,

Weaver,

Roman

et al. 2024

J of Comparative Neurology

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SUMMARYOne of the most important goals in biomedical sciences is understanding the causal mechanisms of neurodegeneration. A prevalent hypothesis relates to impaired waste clearance mechanisms from the brain due to reported waste aggregation in the brains of Alzheimer patients, including amyloid‐β plaques and neurofibrillary tau tangles. Currently, our understanding of the mechanisms by which waste is removed from the brain is only fragmentary. Here we provide compelling evidence that waste clearance from brain tissue is highly conserved in arachnids and humans. Utilizing RNAscope in situ hybridization, immunohistochemical, ultrastructural, and histological approaches, we demonstrate that cellular debris in spider neurons is engulfed by myelin‐forming ependymal glial cells that transect into neuronal somata and form myelin‐derived waste‐internalizing receptacles. These canal systems channel this debris into the lymphatic system likely in an aquaporin‐4 (AQP4) water channel‐dependent manner. We provide robust evidence that a similar process may be true in human hippocampus where vast numbers of myelinated AQP4‐immunoreactive ependymal glial cells send cellular projections into the somata of neurons and glial cells where they differentiate into waste internalizing receptacles. In the brains of Alzheimer decedents, hypertrophic impairment of these myelinated glial cells leads to the catastrophic obstruction and depletion of neuronal cytoplasm into the ependymal glial cells. At the cellular level, the structural impairment of macroglia leads to swelling myelin protrusions that appear as electron‐lucent circular profiles, explaining spongiform abnormalities associated with the neurodegenerative diseases described here. We propose to term this novel type of macroglia‐mediated cell death “gliaptosis.”

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Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer’s Disease

Cited by 6 publications

References 49 publications

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

A Combination of Heavy Metals and Intracellular Pathway Modulators Induces Alzheimer Disease-like Pathologies in Organotypic Brain Slices

Myelinated Glial Cells: Their Proposed Role in Waste Clearance and Neurodegeneration in Arachnid and Human Brain

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