Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation

AbstractPresenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.

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APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

International Journal of Molecular Sciences ◽

10.3390/ijms21041413 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1413 ◽

Cited By ~ 3

Author(s):

Takami Tomiyama ◽

Hiroyuki Shimada

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Fibrils ◽

Synaptic Function ◽

Recessive Inheritance ◽

Familial Alzheimer’S Disease ◽

Aβ Oligomers ◽

Unique Character ◽

Familial Alzheimer's Disease

Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer’s disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer’s disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant’s phenotypes, and propose a mechanism of its recessive inheritance.

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Heavy Tau Burden with Subtle Amyloid β Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer’s Disease with APP Osaka Mutation

International Journal of Molecular Sciences ◽

10.3390/ijms21124443 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4443

Author(s):

Hiroyuki Shimada ◽

Shinobu Minatani ◽

Jun Takeuchi ◽

Akitoshi Takeda ◽

Joji Kawabe ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Cortex ◽

Neuronal Degeneration ◽

Senile Plaques ◽

Amyloid Β ◽

Familial Alzheimer’S Disease ◽

Pet Tracer ◽

Familial Alzheimer's Disease ◽

Parietal Cortices

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer’s disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer’s disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.

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Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications

Current Opinion in Neurobiology ◽

10.1016/j.conb.2020.01.011 ◽

2020 ◽

Vol 61 ◽

pp. 73-81 ◽

Cited By ~ 1

Author(s):

Johannes Trambauer ◽

Akio Fukumori ◽

Harald Steiner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Familial Alzheimer’S Disease ◽

Therapeutic Implications ◽

Familial Alzheimer's Disease ◽

Aβ Generation

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Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer’s Disease

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-210011 ◽

2021 ◽

pp. 1-12

Author(s):

Matthew John Mold ◽

Adam O’Farrell ◽

Benjamin Morris ◽

Christopher Exley

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Senile Plaques ◽

Amyloid Β ◽

Amyloid Β Protein ◽

Phosphorylated Tau ◽

Familial Alzheimer’S Disease ◽

Therapeutic Benefits ◽

Familial Alzheimer's Disease

Background: Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD. Objective: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred. Methods: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method. Results: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques. Conclusion: These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.

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