scholarly journals 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

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.

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

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.

The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid β-protein gene

Nature ◽  
1987 ◽  
Vol 329 (6135) ◽  
pp. 156-157 ◽  
Author(s):  
Rudolph E. Tanzi ◽  
Peter H. St George-Hyslop ◽  
Jonathan L. Haines ◽  
Ronald J. Polinsky ◽  
Linda Nee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Gene ◽  
Genetic Defect ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Familial Alzheimer’S Disease ◽  
Β Protein ◽  
Familial Alzheimer's Disease

scholarly journals Cerebellar Amyloid-β Plaques: Disturbed Cortical Circuitry in AβPP/PS1 Transgenic Mice as a Model of Familial Alzheimer's Disease

2012 ◽  
Vol 31 (2) ◽  
pp. 285-300 ◽  
Author(s):  
Selene Lomoio ◽  
Irene López-González ◽  
Ester Aso ◽  
Margarita Carmona ◽  
Benjamín Torrejón-Escribano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Familial Alzheimer’S Disease ◽  
Cortical Circuitry ◽  
Familial Alzheimer's Disease

scholarly journals Effects of Familial Alzheimer’s Disease Mutations on the Folding Nucleation of the Amyloid β-Protein

2008 ◽  
Vol 381 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Mary Griffin Krone ◽  
Andrij Baumketner ◽  
Summer L. Bernstein ◽  
Thomas Wyttenbach ◽  
Noel D. Lazo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Familial Alzheimer’S Disease ◽  
Disease Mutations ◽  
Β Protein ◽  
Familial Alzheimer's Disease

scholarly journals Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease

2015 ◽  
Vol 212 (12) ◽  
pp. 2003-2013 ◽  
Author(s):  
Maria Szaruga ◽  
Sarah Veugelen ◽  
Manasi Benurwar ◽  
Sam Lismont ◽  
Diego Sepulveda-Falla ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Common Denominator ◽  
Activity Levels ◽  
Familial Alzheimer’S Disease ◽  
Secretase Activity ◽  
Constant Feature ◽  
Familial Alzheimer's Disease ◽  
And Control

Presenilin (PSEN) pathogenic mutations cause familial Alzheimer’s disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall γ-secretase activity levels, and therefore, loss of overall (endopeptidase) γ-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (γ-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like γ-secretase activity with γ-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like γ-secretase activities. However and interestingly, a few SAD patient samples display γ-secretase dysfunction, suggesting that γ-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-β (Aβ) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aβ products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.

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