scholarly journals Neuropathology of Aging in Cats and its Similarities to Human Alzheimer’s Disease

2021 ◽  
Vol 2 ◽  
Author(s):  
Lorena Sordo ◽  
Alessandra C. Martini ◽  
E. Fiona Houston ◽  
Elizabeth Head ◽  
Danièlle Gunn-Moore
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Age Related ◽  
Cat Brain ◽  
Amyloid Aβ ◽  
Intraneuronal Aβ

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

Exploring the Potential of Neuroproteomics in Alzheimer's Disease

2020 ◽  
Vol 20 (25) ◽  
pp. 2263-2278 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Jakaria ◽  
Eduardo Sobarzo-Sánchez ◽  
George E. Barreto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Senile Plaques ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Clinical Expression ◽  
Underlying Processes ◽  
With Memory

Alzheimer's disease (AD) is progressive brain amyloidosis that damages brain regions associated with memory, thinking, behavioral and social skills. Neuropathologically, AD is characterized by intraneuronal hyperphosphorylated tau inclusions as neurofibrillary tangles (NFTs), and buildup of extracellular amyloid-beta (Aβ) peptide as senile plaques. Several biomarker tests capturing these pathologies have been developed. However, for the full clinical expression of the neurodegenerative events of AD, there exist other central molecular pathways. In terms of understanding the unidentified underlying processes for the progression and development of AD, a complete comprehension of the structure and composition of atypical aggregation of proteins is essential. Presently, to aid the prognosis, diagnosis, detection, and development of drug targets in AD, neuroproteomics is elected as one of the leading essential tools for the efficient exploratory discovery of prospective biomarker candidates estimated to play a crucial role. Therefore, the aim of this review is to present the role of neuroproteomics to analyze the complexity of AD.

scholarly journals Changes in the ageing brain in health and disease

1997 ◽  
Vol 352 (1363) ◽  
pp. 1781-1792 ◽  
Author(s):  
Brian H. Anderton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Senile Plaques ◽  
Brain Regions ◽  
Granulovacuolar Degeneration ◽  
Hirano Bodies ◽  
Age Related ◽  
Brain Ageing ◽  
Ageing Brain

The brains of individuals, who are cognitively normal, show age–related changes that include an overall reduction in brain volume and weight, which are associated with gyral atrophy and widening of the sulci of the cerebral cortex, and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. Microscopically, there are increasing amounts of the age–related pigment, lipofuscin, granulovacuolar degeneration in neurons, Hirano bodies, variable amounts of diffuse deposits of β–amyloid in the parenchyma, the presence of neurofibrillary tangles mainly confined to the hippocampus and amygdala, and sparse numbers of senile plaques in these brain regions and also in other cortical areas. Of these changes, neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread. Alzheimer's disease has therefore been regarded as accelerated brain ageing; however, the realization that there is a strong genetic contribution to developing the disease at least implies that it may not be the inevitable, even if frequent, consequence of old age. Understanding the molecular basis of plaque and tangle formation is advancing greatly and is the main focus of research into the cellular and molecular changes observed in the ageing brain.

Preclinical Cognitive Trajectories Differ for Alzheimer's Disease and Vascular Dementia

2012 ◽  
Vol 18 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Erika J. Laukka ◽  
Stuart W.S. MacDonald ◽  
Laura Fratiglioni ◽  
Lars Bäckman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Early Stage ◽  
Block Design ◽  
Word Recall ◽  
Cognitive Tasks ◽  
Control Group ◽  
Age Related ◽  
Preclinical Ad

AbstractWe investigated differences between Alzheimer's disease (AD) and vascular dementia (VaD) from the appearance of the first cognitive symptoms, focusing on both time of onset and rate of accelerated decline for different cognitive functions before dementia diagnosis. Data from a longitudinal population-based study were used, including 914 participants (mean age = 82.0 years, SD = 5.0) tested with a cognitive battery (word recall and recognition, Block Design, category fluency, clock reading) on up to four occasions spanning 10 years. We fit a series of linear mixed effects models with a change point to the cognitive data, contrasting each dementia group to a control group. Significant age-related decline was observed for all five cognitive tasks. Relative to time of diagnosis, the preclinical AD persons deviated from the normal aging curve earlier (up to 9 years) compared to the preclinical VaD persons (up to 6 years). However, once the preclinical VaD persons started to decline, they deteriorated at a faster rate than the preclinical AD persons. The results have important implications for identifying the two dementia disorders at an early stage and for selecting cognitive tasks to evaluate treatment effects for persons at risk of developing AD and VaD. (JINS, 2012, 18, 191–199)

scholarly journals RNA and Oxidative Stress in Alzheimer’s Disease: Focus on microRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Akihiko Nunomura ◽  
George Perry
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Early Stage ◽  
Brain Regions ◽  
Prodromal Stage ◽  
Adaptive Mechanisms ◽  
Therapeutic Tools ◽  
Key Events

Oxidative stress (OS) is one of the major pathomechanisms of Alzheimer’s disease (AD), which is closely associated with other key events in neurodegeneration such as mitochondrial dysfunction, inflammation, metal dysregulation, and protein misfolding. Oxidized RNAs are identified in brains of AD patients at the prodromal stage. Indeed, oxidized mRNA, rRNA, and tRNA lead to retarded or aberrant protein synthesis. OS interferes with not only these translational machineries but also regulatory mechanisms of noncoding RNAs, especially microRNAs (miRNAs). MiRNAs can be oxidized, which causes misrecognizing target mRNAs. Moreover, OS affects the expression of multiple miRNAs, and conversely, miRNAs regulate many genes involved in the OS response. Intriguingly, several miRNAs embedded in upstream regulators or downstream targets of OS are involved also in neurodegenerative pathways in AD. Specifically, seven upregulated miRNAs (miR-125b, miR-146a, miR-200c, miR-26b, miR-30e, miR-34a, miR-34c) and three downregulated miRNAs (miR-107, miR-210, miR-485), all of which are associated with OS, are found in vulnerable brain regions of AD at the prodromal stage. Growing evidence suggests that altered miRNAs may serve as targets for developing diagnostic or therapeutic tools for early-stage AD. Focusing on a neuroprotective transcriptional repressor, REST, and the concept of hormesis that are relevant to the OS response may provide clues to help us understand the role of the miRNA system in cellular and organismal adaptive mechanisms to OS.

scholarly journals Entropy and Complexity Analyses in Alzheimer’s Disease: An MEG Study

2010 ◽  
Vol 4 (1) ◽  
pp. 223-235 ◽  
Author(s):  
Carlos Gómez ◽  
Roberto Hornero
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fractal Dimension ◽  
Background Activity ◽  
Senile Plaques ◽  
Approximate Entropy ◽  
Brain Regions ◽  
Brain Disorder ◽  
Complexity Measures ◽  
Control Subjects

Alzheimer’s disease (AD) is one of the most frequent disorders among elderly population and it is considered the main cause of dementia in western countries. This irreversible brain disorder is characterized by neural loss and the appearance of neurofibrillary tangles and senile plaques. The aim of the present study was the analysis of the magnetoencephalogram (MEG) background activity from AD patients and elderly control subjects. MEG recordings from 36 AD patients and 26 controls were analyzed by means of six entropy and complexity measures: Shannon spectral entropy (SSE), approximate entropy (ApEn), sample entropy (SampEn), Higuchi’s fractal dimension (HFD), Maragos and Sun’s fractal dimension (MSFD), and Lempel-Ziv complexity (LZC). SSE is an irregularity estimator in terms of the flatness of the spectrum, whereas ApEn and SampEn are embbeding entropies that quantify the signal regularity. The complexity measures HFD and MSFD were applied to MEG signals to estimate their fractal dimension. Finally, LZC measures the number of different substrings and the rate of their recurrence along the original time series. Our results show that MEG recordings are less complex and more regular in AD patients than in control subjects. Significant differences between both groups were found in several brain regions using all these methods, with the exception of MSFD (p-value < 0.05, Welch’s t-test with Bonferroni’s correction). Using receiver operating characteristic curves with a leave-one-out cross-validation procedure, the highest accuracy was achieved with SSE: 77.42%. We conclude that entropy and complexity analyses from MEG background activity could be useful to help in AD diagnosis.

scholarly journals Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

2016 ◽  
Vol 2016 ◽  
pp. 1-19 ◽  
Author(s):  
Sung-Soo Jang ◽  
Hee Jung Chung
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Senile Plaques ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Homeostatic Plasticity ◽  
Brain Disorder

Alzheimer’s disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β(Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβoligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβlevels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

scholarly journals The Triggering Receptor Expressed on Myeloid Cells 2: “TREM-ming” the Inflammatory Component Associated with Alzheimer's Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Troy T. Rohn
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Senile Plaques ◽  
Myeloid Cells ◽  
Disease Process ◽  
Age Related

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. TREM2 is expressed on microglial cells, the resident macrophages in the CNS, and functions to stimulate phagocytosis on one hand and to suppress cytokine production and inflammation on the other hand. The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS. In this context, an overview of the pathways linking beta-amyloid, neurofibrillary tangles (NFTs), oxidative stress, and inflammation will be discussed.

scholarly journals Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

2021 ◽  
Vol 7 (25) ◽  
pp. eabg4855
Author(s):  
Wojciech Michno ◽  
Katie M. Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mass Spectrometry Imaging ◽  
Isotope Labeling ◽  
Brain Regions ◽  
Plaque Development ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Detailed Picture

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

scholarly journals Tau seeding activity anticipates phospho-tau pathology in Alzheimer’s disease

2018 ◽  
Author(s):  
Sarah K. Kaufman ◽  
Kelly Del Tredici ◽  
Talitha L. Thomas ◽  
Heiko Braak ◽  
Marc I. Diamond
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Visual Cortex ◽  
Brain Regions ◽  
Tau Pathology ◽  
Age Related ◽  
Important Addition ◽  
Disease Stages ◽  
Relationship Of ◽  
The Relationship

AbstractAlzheimer’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n=247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the first temporal gyrus and visual cortex at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC, and may offer an important addition to classical histopathology.

scholarly journals Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer’s Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9205
Author(s):  
Amaya Urdánoz-Casado ◽  
Javier Sánchez-Ruiz de Gordoa ◽  
Maitane Robles ◽  
Blanca Acha ◽  
Miren Roldan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Circular Rna ◽  
Brain Regions ◽  
Mrna Levels ◽  
C Protein ◽  
Amyloid Aβ ◽  
Cortical Regions ◽  
Female Specific

The HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer’s disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with β-Amyloid (Aβ) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aβ deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.

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