Neurofibrillary tangle distribution in the cerebral cortex of parkinsonism-dementia cases from Guam: differences with Alzheimer's disease

AbstractAlzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.

Download Full-text

Amyloid-beta peptide and phosphorylated tau in the frontopolar cerebral cortex and in the cerebellum of toothed whales: aging vs hypoxia

10.21203/rs.3.rs-17031/v1 ◽

2020 ◽

Author(s):

Simona Sacchini ◽

Josué Díaz ◽

Antonio Espinosa de los Monteros ◽

Yania Paz ◽

Yara Bernaldo de Quirós ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Cortex ◽

Neurodegenerative Diseases ◽

Cortical Neurons ◽

Neurofibrillary Tangle ◽

Immunohistochemical Analysis ◽

Granulovacuolar Degeneration ◽

Beaked Whales ◽

The Brain

Abstract Background: Alzheimer’s disease results from the interplay of multiple risk factors and their effects. Diving mammals may be routinely exposed to severe hypoxia when submerged. Among toothed whales, the beaked whales are particularly cryptic and routinely dive deeper than 1,000 m for about one hour in order to hunt deep-water squid and fish. We hypothesized that hypoxia could be a possible risk factor for neurodegenerative alterations in the central nervous system of beaked whales in particular, and toothed whales in general. Results: Samples of frontal cerebral cortex and cerebellum were collected from nine animals, representing six different species of the suborder Odontoceti. Immunohistochemical analysis employed a monoclonal anti-β-amyloid (Aβ) and a polyclonal anti-neurofibrillary tangle (NFT) antibodies. Six of nine (67%) animals showed positive immunolabeling for Aβ and/or NFT. The most striking findings were intranuclear Aβ immunopositivity in cerebral cortical neurons and NFT immunopositivity in cerebellar Purkinje neurons with granulovacuolar degeneration. Herein, we present immunohistopathological findings classic of Alzheimer’s and other neurodegenerative diseases in humans, in different brain locales of odontocete cetaceans. This study represents the first description of Aβ and NFT in the brain of beaked whales, adding also to the non-existent descriptions of GVD in the brain of non-experimental animals, being specifically the first report of granulovacuolar degeneration in the cerebellum. Our results further confirm the rarely reported intranuclear expression of Aβ. Conclusions: These findings could be linked to hypoxic phenomena, as they were more extensive in the brains of beaked whales, and not only in aged individuals. Therefore, a novel hypothesis linking hypoxia and neurodegeneration microscopic hallmarks in cetaceans is proposed. Despite their adaptations, diving mammals could be vulnerable to sustained and repetitive brain hypoxia. Future comparative pathological and neuroprotective investigations may prove of great value to Alzheimer’s disease and other neurodegenerative diseases in humans.

Download Full-text

Disruption of a RAC1-centred network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

Human Molecular Genetics ◽

10.1093/hmg/ddz320 ◽

2020 ◽

Vol 29 (5) ◽

pp. 817-833 ◽

Cited By ~ 1

Author(s):

Masataka Kikuchi ◽

Michiko Sekiya ◽

Norikazu Hara ◽

Akinori Miyashita ◽

Ryozo Kuwano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Model ◽

Neurofibrillary Tangle ◽

Neuronal Cell ◽

Brain Regions ◽

Protein Domain ◽

Expression Data ◽

Integrated Network ◽

Age Dependent

Abstract The molecular biological mechanisms of Alzheimer’s disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

Download Full-text

Alzheimer's disease-type neurofibrillary degeneration in verrucose dysplasias of the cerebral cortex

Acta Neuropathologica ◽

10.1007/bf00315009 ◽

1995 ◽

Vol 90 (4) ◽

pp. 356-365 ◽

Cited By ~ 5

Author(s):

M. A. Mor�n ◽

A. Probst ◽

C. Navarro ◽

P. G�mez-Ramos

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Cortex ◽

Disease Type ◽

Neurofibrillary Degeneration

Download Full-text

Intralaminar Distribution of Neurotransmitter-Related Enzymes in Cerebral Cortex of Alzheimer’s Disease

Gerontology ◽

10.1159/000212876 ◽

1987 ◽

Vol 33 (3-4) ◽

pp. 197-202 ◽

Cited By ~ 8

Author(s):

Sandro Sorbi ◽

Silvia Piacentini ◽

Luigi Amaducci

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Cortex

Download Full-text

Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-210059 ◽

2021 ◽

pp. 1-10

Author(s):

Douglas Barthold ◽

Laura E. Gibbons ◽

Zachary A. Marcum ◽

Shelly L. Gray ◽

C. Dirk Keene ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Education ◽

Descriptive Analysis ◽

Neurofibrillary Tangle ◽

Apoe Genotype ◽

Severity Index ◽

Neuritic Plaque ◽

Braak Stage ◽

Total N

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Download Full-text