Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Lee, Ju‐Hyun; Yang, Dun‐Sheng; Goulbourne, Chris N.; Im, Eunju; Stavrides, Philip; Pensalfini, Anna; Chan, Han; Bouchet‐Marquis, Cédric; Bleiwas, Cynthia; Berg, Martin J.; Huo, Chunfeng; Peddy, James; Pawlik, Monika; Levy, Efrat; Rao, M. Narayana; Staufenbiel, M; Nixon, Ralph A.

doi:10.1038/s41593-022-01084-8

Cited by 387 publications

(349 citation statements)

References 61 publications

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“…A recent study suggests that cored deposits may originate from Aβ aggregates that initially form within endosomal/lysosomal compartments [ 42 ]. It is not known whether diffuse deposits could also originate in intracellular compartments.…”

Section: Discussionmentioning

confidence: 99%

Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

Fromholt

Borchelt

2022

Biomolecules

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The amyloid pathology characteristic of Alzheimer’s disease (AD) can be broadly classified as either fibrillary amyloid or diffuse amyloid. Fibrillary amyloid is found in cored-neuritic deposits, fibrillar deposits, and vascular deposits, and binds strongly to the amyloid revealing dyes Thioflavin-S or Congo Red. Diffuse amyloid can appear as wispy dispersed deposits or compact tufted deposits dispersed in neuropil, and binds amyloid dyes weakly if at all. In AD brains, both types of pathology are detected. Homogenates from AD brains, or the brains of transgenic mice modeling AD-amyloidosis, have been used to seed pathology in vulnerable host transgenic models. These studies suggest that pathologies may arise from distinct conformers or strains of misfolded Aβ, similar to propagating prions. Using Aβ strains sourced from four different AD-amyloidosis models, we injected pathological seeds into the brains of newborn mice from three different transgenic hosts with distinctive Aβ pathologies. Two of the seeding sources were from mice that primarily develop cored-neuritic Aβ deposits (cored strain) while the other two seeding sources were from mice that develop diffuse Aβ deposits (diffuse strain). These seeds were injected into host APP mice in which the resident strain was either diffuse or cored-neuritic pathology. Seeding-homogenates were injected into the brains of newborn mice to initiate propagation as early as possible. Depending upon the level of transgene expression in the host, we show that the injected strains of misfolded Aβ from the seeding homogenate were able to outcompete the resident strain of the APP host model. In serial passaging experiments, it appeared that the diffuse strain was more easily propagated than the cored strain. Collectively, our studies align with the idea that different types of Aβ pathology in AD brains arise from different populations of Aβ conformers that compete to populate the brain.

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Section: Discussionmentioning

confidence: 99%

Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

Fromholt

Borchelt

2022

Biomolecules

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“…Aβ peptides are generated from the sequential cleavage of APP by β- and γ-secretases within vesicles inside cells and on the plasma membrane, and are normally secreted under physiological conditions [ 42 ]. On the other hand, there is evidence showing the presence of intracellular Aβ, particularly in mouse models of amyloidosis [ 24 , 25 , 26 , 27 , 28 , 29 ], suggesting that some Aβ is retained inside the neurons. However, the detailed properties of intracellular Aβ are not fully established.…”

Section: Discussionmentioning

confidence: 99%

“…In transgenic rodents designed to develop amyloidosis, large amounts of early intraneuronal Aβ were observed prior to the formation of plaques, which could be linked to deficits in synaptic plasticity, learning, and memory [ 27 , 28 ]. A recent study has added a new significant insight that the deficit in the autolysosome acidification, accompanied by the accumulation of C99 and Aβ peptides, is an early event in neurons, and such neurons could be the principal sources of neuritic plaques in amyloidosis models [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons

et al. 2022

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Amyloid-beta (Aβ) peptides are produced within neurons. Some peptides are released into the brain parenchyma, while others are retained inside the neurons. However, the detection of intracellular Aβ remains a challenge since antibodies against Aβ capture Aβ and its precursor proteins (i.e., APP and C99). To overcome this drawback, we recently developed 1) the C99 720-670 biosensor for recording γ-secretase activity and 2) a unique multiplexed immunostaining platform that enables the selective detection of intracellular Aβ with subcellular resolution. Using these new assays, we showed that C99 is predominantly processed by γ-secretase in late endosomes and lysosomes, and intracellular Aβ is enriched in the same subcellular loci in intact neurons. However, the detailed properties of Aβ in the acidic compartments remain unclear. Here, we report using fluorescent lifetime imaging microscopy (FLIM) that intracellular Aβ includes both long Aβ intermediates bound to γ-secretase and short peptides dissociated from the protease complex. Surprisingly, our results also suggest that the dissociated Aβ is bound to the glycoproteins on the inner membrane of lysosomes. Furthermore, we show striking cell-to-cell heterogeneity in intracellular Aβ levels in primary neurons and APP transgenic mouse brains. These findings provide a basis for the further investigation of the role(s) of intracellular Aβ and its relevance to Alzheimer’s disease (AD).

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“…Previous studies have attributed the neuronal damage observed in AD to what happens following the accumulation of β-amyloid (Aβ) outside the cell, rather than before it and inside the neuron. Recent studies have found that the neuronal damage observed in AD may be attributed to the lower activity of lysosomal acidic enzymes in brain cells; before plaques are formed outside the cells, the nerve cells are paralyzed [ 21 ].…”

Section: Possible Triggers and Mechanisms Of Cognitive Decline In The...mentioning

confidence: 99%

Tea Polyphenols as Prospective Natural Attenuators of Brain Aging

Hong

Yu²,

Wang³

et al. 2022

Nutrients

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No organism can avoid the process of aging, which is often accompanied by chronic disease. The process of biological aging is driven by a series of interrelated mechanisms through different signal pathways, including oxidative stress, inflammatory states, autophagy and others. In addition, the intestinal microbiota play a key role in regulating oxidative stress of microglia, maintaining homeostasis of microglia and alleviating age-related diseases. Tea polyphenols can effectively regulate the composition of the intestinal microbiota. In recent years, the potential anti-aging benefits of tea polyphenols have attracted increasing attention because they can inhibit neuroinflammation and prevent degenerative effects in the brain. The interaction between human neurological function and the gut microbiota suggests that intervention with tea polyphenols is a possible way to alleviate brain-aging. Studies have been undertaken into the possible mechanisms underpinning the preventative effect of tea polyphenols on brain-aging mediated by the intestinal microbiota. Tea polyphenols may be regarded as potential neuroprotective substances which can act with high efficiency and low toxicity.

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Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Cited by 387 publications

References 61 publications

Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons

Tea Polyphenols as Prospective Natural Attenuators of Brain Aging

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