Cadmium, an Environmental Contaminant, Exacerbates Alzheimer's Pathology in the Aged Mice's Brain.
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ABSTRACT:
SUBMITTER: Ali T
PROVIDER: S-EPMC8263901 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1(-/-) mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1(-/-) mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1(-/-) mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.
| S-EPMC4836404 | biostudies-literature
Project description:Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.
| S-EPMC8841674 | biostudies-literature
Project description:The molecular mechanism of Alzheimer's disease (AD) pathogenesis remains obscure. Life and/or environmental events, such as traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH), are proposed exogenous risk factors for AD. BDNF/TrkB, an essential neurotrophic signaling for synaptic plasticity and neuronal survival, are reduced in the aged brain and in AD patients. Here, we show that environmental factors activate C/EBPβ, an inflammatory transcription factor, which subsequently up-regulates δ-secretase that simultaneously cleaves both APP and Tau, triggering AD neuropathological changes. These adverse effects are additively exacerbated in BDNF+/- or TrkB+/- mice. Strikingly, TBI provokes both senile plaque deposit and neurofibrillary tangles (NFT) formation in TrkB+/- mice, associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits. Depletion of C/EBPβ inhibits TBI-induced AD-like pathologies in these mice. Remarkably, amyloid aggregates and NFT are tempospatially distributed in TrkB+/- mice brains after TBI, providing insight into their spreading in the progression of AD-like pathologies. Hence, our study revealed the roles of exogenous (TBI, HFD, and CCH) and endogenous (TrkB/BDNF) risk factors in the onset of AD-associated pathologies.
| S-EPMC8237621 | biostudies-literature
Project description:Essentials Evidence suggests a comorbidity between hyperhomocysteinemia (HHC) and Alzheimer's disease (AD). Homocysteine (HC) could affect the ?-amyloid (A?)-fibrinogen interaction in AD pathology. AD patients with concomitant HHC have increased fibrin and A? deposits in their brains. HC contributes to AD pathology via the A?-fibrinogen interaction.Background Accumulating clinical evidence suggests that hyperhomocysteinemia (HHC) is correlated with Alzheimer's disease (AD) and vascular dementia. Objective This study was carried out to elucidate the specific role of elevated homocysteine (HC) levels in AD pathophysiology. Methods Immunohistochemistry was used to examine ?-amyloid (A?) deposition along blood vessels, also known as cerebral amyloid angiopathy (CAA), fibrin(ogen) deposition, and their correlation to each other in the brains of AD patients with and without HHC. To study AD-HHC co-morbidity in detail, an AD mouse model was administered a high methionine diet for several months. Parenchymal A? plaques, CAA-positive vessels and fibrin deposits were then assessed by immunohistochemistry at different stages of AD progression. Memory deficits were evaluated with contextual fear conditioning and the Barnes maze. Additionally, the effect of HC and its metabolite, homocysteine thiolactone (HCTL), on the A?-fibrinogen interaction was analyzed by pull-down, ELISA and fibrin clot formation and fibrinolysis assays in vitro. Results We found increased fibrin(ogen) levels and A? deposits in the blood vessels and brain parenchyma of AD patients with HHC. We demonstrate that HC and HCTL enhance the interaction between fibrinogen and A?, promote the formation of tighter fibrin clots and delay clot fibrinolysis. Additionally, we show that diet-induced HHC in an AD mouse model leads to severe CAA and parenchymal A? deposition, as well as significant impairments in learning and memory. Conclusions These findings suggest that elevated levels of plasma HC/HCTL contribute to AD pathology via the A?-fibrin(ogen) interaction.
| S-EPMC4949110 | biostudies-literature
Project description:Alzheimer's disease (AD) is mainly characterized by the accumulation and aggregation of amyloid-? (A?) peptides in brain parenchyma and cerebral microvasculature. Unfortunately, the exact causes of the disease are still unclear. However, blood-brain barrier (BBB) dysfunction and activation of inflammatory pathways are implicated in AD pathogenesis. Importantly, advanced age and high fat diet, two major risk factors associated with AD, were shown to deeply affect BBB function and modulate the immune response. As such, this study evaluated the impact of age and high fat diet on AD progression. For this purpose, 3 (i.e. young) and 12 (i.e. aged) months old APPswe/PS1 mice were fed for 4 months with a high fat diet (i.e. Western diet (WD)) or normal diet. Interestingly, neurobehavioral tests revealed that WD accelerates age-associated cognitive decline without affecting parenchymal A?. Nonetheless, WD decreases matrix metalloproteinase-9 enzymatic activity and brain-derived neurotrophic factor mRNA and protein levels in brain, suggesting loss of synaptic plasticity. In the periphery, WD promotes systemic inflammation by increasing the levels of blood-circulating monocytes and monocyte chemotactic protein-1 production, which is accompanied by an augmentation of oxidized-low density lipoprotein levels in blood circulation. At the BBB, WD potentiates the age-induced increase of A? 1-40 accumulation and exacerbates the oxidative stress, specifically in cerebral microvasculature. These effects were accompanied by the dysfunction of pericytes, thus altering BBB functionality without compromising its integrity. Our study provides new insights into the implication of high fat diet in accelerating the cognitive decline in AD.
| S-EPMC5356521 | biostudies-literature
Project description:Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ?-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M(1) receptors (M(1)Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M(1)Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M(1)R(-/-) mice. Our data show that M(1)R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M(1)R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A? in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M(1)R were attributed to changes in the glycogen synthase kinase 3? and protein kinase C activities. Finally, deleting the M(1)R increased the astrocytic and microglial response associated with A? plaques. Our data highlight the significant role that disrupting the M(1)R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M(1)R agonists for treating AD.
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Project description:The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on Abeta accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on Abeta and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of alpha7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of alpha7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal Abeta(42) accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either Abeta or tau.
| S-EPMC549455 | biostudies-literature
Project description:The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic beta-amyloid (Abeta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.
| S-EPMC2486412 | biostudies-other
Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.
2024-02-01 | GSE254650 | GEO
Project description:Deposition of amyloid-? (A?) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived A? degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive A? pathology in AD model mice. The expression of Klk7 was upregulated by A? treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by A?-induced responses. Finally, we found that the Food and Drug Administration-approved anti-dementia drug memantine can increase the expression of Klk7 and A? degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited A? species by astrocytes involved in the pathogenesis of AD.
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