scholarly journals MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-30
Author(s):  
Yuri Mizuno ◽  
Nona Abolhassani ◽  
Guianfranco Mazzei ◽  
Kunihiko Sakumi ◽  
Takashi Saito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mammalian Cells ◽  
Hippocampal Neurons ◽  
Memory Impairment ◽  
Amyloid Β ◽  
Neurodegenerative Process ◽  
Preclinical Ad ◽  
Impaired Neurogenesis

Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

scholarly journals Nature of the neurotoxic membrane actions of amyloid-β on hippocampal neurons in Alzheimer's disease

2014 ◽  
Vol 35 (3) ◽  
pp. 472-481 ◽  
Author(s):  
Fernando J. Sepúlveda ◽  
Humberto Fierro ◽  
Eduardo Fernandez ◽  
Carolina Castillo ◽  
Robert W. Peoples ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Amyloid Β

Melatonin Attenuates Memory Impairment, Amyloid-β Accumulation, and Neurodegeneration in a Rat Model of Sporadic Alzheimer’s Disease

2015 ◽  
Vol 47 (1) ◽  
pp. 103-116 ◽  
Author(s):  
Ekaterina A. Rudnitskaya ◽  
Natalia A. Muraleva ◽  
Kseniya Yi. Maksimova ◽  
Elena Kiseleva ◽  
Nataliya G. Kolosova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Memory Impairment ◽  
Amyloid Β ◽  
Sporadic Alzheimer’S Disease

scholarly journals Ameliorative effects of olibanum essential oil on learning and memory in Aβ1-42-induced Alzheimer’s disease mouse model

2020 ◽  
Vol 19 (8) ◽  
pp. 1643-1651
Author(s):  
Zhenzhen Zhang ◽  
Wenhua Chen ◽  
Jie Luan ◽  
Dagui Chen ◽  
Lina Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
Learning And Memory ◽  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Morris Water Maze Test ◽  
Amyloid Β Peptide ◽  
Brain Tissues

Purpose: To study the effect of olibanum essential oil (OEO) on learning and memory in Alzheimer’s disease (AD) mouse.Methods: Mice were administered the 42-amino acid form of amyloid β-peptide (Aβ1-42) to induce AD and then treated with OEO at 150, 300, and 600 mg/kg, p.o. for two weeks. Following treatment, the AD mice were assessed by step-down test (SDT), dark avoidance test (DAT), and Morris water maze test (MWM). Blood and brain tissues were collected for biochemical assessments. Gas chromatographymass spectroscopy was used to analyze the main constituents of OEO.Results: The main constituents of OEO were limonene, α-pinene, and 4-terpineol. Treatment with OEO prolonged t latency in SDT and DAT, but decreased error times. Escape latency decreased and crossing times were rose in the MWM following OEO treatment (p < 0.5). Treatment with OEO also enhanced the acetylcholine levels and decreased the acetylcholinesterase levels in serum and brain tissue (p < 0.5). Additionally, OEO reduced amyloid plaques in the hippocampus and protected hippocampal neurons from damage. Furthermore, OEO decreased c-fos expression in  hippocampus tissues from AD mice (p < 0.5).Conclusion: OEO has significant ameliorative effect AD-induced deterioration in learning and memory in AD mouse induced by Aβ1-42. The mechanisms of these effects are related to increased acetylcholine contents, reduction of amyloid plaques, protection of hippocampal neurons, and downregulation of c-fos in brain tissues. The results justify the need for further investigation of candidate drugs derived from OEO for the  management of AD. Keywords: Olibanum, Essential oil, Learning, Memory, AD

scholarly journals Alzheimer's disease and sleep disturbances: a review

2019 ◽  
Vol 77 (11) ◽  
pp. 815-824 ◽  
Author(s):  
Conrado Regis Borges ◽  
Dalva Poyares ◽  
Ronaldo Piovezan ◽  
Ricardo Nitrini ◽  
Sonia Brucki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Sleep Disturbances ◽  
Neurodegenerative Process ◽  
Preclinical Ad ◽  
Scientific Attention ◽  
Meta Analyses ◽  
The Impact

ABSTRACT The association between Alzheimer's disease (AD) and sleep disturbances has received increasing scientific attention in the last decades. However, little is known about the impact of sleep and its disturbances on the development of preclinical AD stages, such as mild cognitive impairment. This review describes the evolution of knowledge about the potential bidirectional relationships between AD and sleep disturbances exploring recent large prospective studies and meta-analyses and studies of the possible mechanisms through which sleep and the neurodegenerative process could be associated. The review also makes a comprehensive exploration of the sleep characteristics of older people, ranging from cognitively normal individuals, through patients with mild cognitive impairment, up to the those with dementia with AD.

scholarly journals Alzheimer’s disease: A matter of blood–brain barrier dysfunction?

2017 ◽  
Vol 214 (11) ◽  
pp. 3151-3169 ◽  
Author(s):  
Axel Montagne ◽  
Zhen Zhao ◽  
Berislav V. Zlokovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Neurodegenerative Process ◽  
Blood Brain ◽  
Underlying Mechanisms

The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.

Sign in / Sign up

Export Citation Format

Share Document