scholarly journals Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Angie K. Torres ◽  
Claudia Jara ◽  
Margrethe A. Olesen ◽  
Cheril Tapia-Rojas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Brain Aging ◽  
Memory Loss ◽  
Proteinase K ◽  
Immunogold Electron Microscopy ◽  
Phosphorylated Tau ◽  
Aged Mice ◽  
Age Related ◽  
Synaptic Failure ◽  
Synaptic Mitochondria

AbstractBrain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.

scholarly journals Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

2021 ◽  
Author(s):  
Sujeong Yang ◽  
Sylvain Gigout ◽  
Angelo Molinaro ◽  
Yuko Naito-Matsui ◽  
Sam Hilton ◽  
...  
Keyword(s):  
Chondroitin Sulphate ◽  
Memory Loss ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Aged Mice ◽  
Age Related ◽  
Term Potentiation ◽  
Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

scholarly journals Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Martina Reutzel ◽  
Rekha Grewal ◽  
Carmina Silaidos ◽  
Jens Zotzel ◽  
Stefan Marx ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Citrate Synthase ◽  
Brain Aging ◽  
Mrna Levels ◽  
Nmri Mice ◽  
Aged Mice ◽  
Atp Levels ◽  
Long Term Treatment ◽  
The Brain

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer’s disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

scholarly journals Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss

2020 ◽  
Author(s):  
Claudia Jara ◽  
Angie K. Torres ◽  
Margrethe A. Olesen ◽  
Cheril Tapia-Rojas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Memory Loss ◽  
Synaptic Failure

scholarly journals A Walnut-Enriched Diet Modifies the Oxylipin Profile in Liver and Brain of Aged Mice — Impact on Inflammation Markers

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1203-1203
Author(s):  
Gunter Eckert ◽  
Gunter Esselun ◽  
Elisabeth Koch ◽  
Nils Schebb
Keyword(s):  
Physical Activity ◽  
Fatty Acids ◽  
Brain Aging ◽  
Inflammatory Marker ◽  
Inflammation Markers ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Abstract Objectives Neuroinflammation contributes to brain-aging which may be mitigated by anti-inflammatory oxylipins. Based on our previous findings that a 6% walnut-enriched diet alone, and additional physical activity (PA), enhanced cognition in 18 months old NMRI, we now investigated the effects of this diet on oxylipin- and inflammatory marker levels in liver and brain. Methods 18 months and 3 months old female NMRI mice were fed with a 6% walnut-enriched diet. Oxylipins were determined in brain and liver sections using LC-MS. Expression of IL1β gene was determined by qRT-PCR. Results The walnut diet compensates for the age related increase in IL1β gene expression in the liver of mice, whereas expression in the brain was not affected. Basal levels of oxylipins in brain and liver samples isolated from young mice were generally lower compared to aged mice. The walnut diet further increased oxylipin levels of walnut specific fatty acids in liver and brain of aged mice. Enrichment of linoleic acid (LA) and α-linolenic acid (ALA) derived oxylipin levels were quantitatively higher in the liver compared to the brain (P < 0.0001). Hydroxy-oxylipins (HO) based on fatty acid LA were significantly increased in brain (P < 0.001) and liver (P < 0.0001) compared to control mice, while ALA based HO were only detected in the brains of walnut fed mice. The walnut diet in combination with physical activity (PA) reduced ARA based oxylipin levels (P < 0.05). Across all groups, concentrations of prostanoids were higher in the brain as compared to liver (P < 0.001). In the liver, walnuts tended to decrease PGD2 and TxB2 levels while increasing 6-keto PGF1α. The latter, as well as TxB2 tended to be decreased in the brain. Other ARA based prostanoids were unaffected. Effects of PA were contrary to each other, tending to increase ARA based prostanoids in the liver while decreasing them in the brain. PA further enhanced this effect in the brain, but tended to increase the inflammatory response in the liver. Conclusions A walnut diet differentially affects the oxylipin profile of liver and brain in aged mice. Production of oxylipins based on walnut fatty acids is generally increased. Attenuation of age-related, chronic inflammation in might be one of walnut's benefits and may contribute to a healthier aging of the brain. Funding Sources Research was supported by grants from California Walnut Commission.

scholarly journals Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain

Science ◽  
2020 ◽  
Vol 369 (6500) ◽  
pp. 167-173 ◽  
Author(s):  
Alana M. Horowitz ◽  
Xuelai Fan ◽  
Gregor Bieri ◽  
Lucas K. Smith ◽  
Cesar I. Sanchez-Diaz ◽  
...  
Keyword(s):  
Brain Aging ◽  
Plasma Concentrations ◽  
Signaling Cascades ◽  
Aged Mice ◽  
Beneficial Effects ◽  
Healthy Elderly ◽  
Age Related ◽  
Phospholipase D1 ◽  
Elderly Humans ◽  
Blood Factors

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer’s Disease

2021 ◽  
pp. 1-24
Author(s):  
Angie K. Torres ◽  
Claudia Jara ◽  
Han S. Park-Kang ◽  
Catalina M. Polanco ◽  
Diego Tapia ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurofibrillary Tangles ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Aβ Peptide ◽  
Predisposing Factor ◽  
Age Related ◽  
Synaptic Mitochondria

Alzheimer’s disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.

scholarly journals Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Debora Cutuli ◽  
Eugenia Landolfo ◽  
Annalisa Nobili ◽  
Paola De Bartolo ◽  
Stefano Sacchetti ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Basal Forebrain ◽  
Brain Aging ◽  
Life Quality ◽  
Cholinergic Neurons ◽  
Hippocampal Neurogenesis ◽  
Omega 3 ◽  
Pufa Supplementation ◽  
Aged Mice ◽  
Age Related

Abstract Background In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.

scholarly journals Restoring the pattern of proteoglycan sulphation in perineuronal nets corrects age-related memory loss

2020 ◽  
Author(s):  
Sujeong Yang ◽  
Sylvain Gigout ◽  
Angelo Molinaro ◽  
Yuko Naito-Matsui ◽  
Sam Hilton ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Memory Loss ◽  
Long Term Potentiation ◽  
Perineuronal Nets ◽  
Transgenic Expression ◽  
Aged Mice ◽  
Age Related ◽  
Term Potentiation ◽  
Early Memory

AbstractMemory loss is a usual consequence of ageing and aged mice show progressive deficits in memory tasks. In aged brains, perineuronal nets (PNNs), which are implicated in plasticity and memory, become inhibitory due to decreased 6-sulphation of their glycan chains (C6S). Removal of PNNs or digestion of their glycosaminoglycans rescued age-related memory loss. Premature reduction of permissive C6S by transgenic deletion of chondroitin 6-sulfotransferase led to very early memory loss. However, restoring C6S levels in aged animals by AAV delivery or transgenic expression of 6-sulfotransferase restored memory. Low C6S levels caused loss of cortical long-term potentiation, which was restored by AAV-mediated 6-sulfotransferase delivery. The study shows that loss of C6S in the aged brain leads to declining memory and cognition. Age-related memory impairment was restored by C6S replacement or other interventions targeting perineuronal nets

scholarly journals Successful brain aging: plasticity, environmental enrichment, and lifestyle

2013 ◽  
Vol 15 (1) ◽  
pp. 45-52 ◽  
Keyword(s):  
Cognitive Deficits ◽  
Successful Aging ◽  
Environmental Enrichment ◽  
Brain Aging ◽  
Memory Loss ◽  
Lifestyle Factors ◽  
Mechanisms Of Action ◽  
Aging Brain ◽  
Age Related ◽  
The Brain

Aging is a physiological process that can develop without the appearance of concurrent diseases. However, very frequently, older people suffer from memory loss and an accelerated cognitive decline. Studies of the neurobiology of aging are beginning to decipher the mechanisms underlying not only the physiology of aging of the brain but also the mechanisms that make people more vulnerable to cognitive dysfunction and neurodegenerative diseases. Today we know that the aging brain retains a considerable functional plasticity, and that this plasticity is positively promoted by genes activated by different lifestyle factors. In this article some of these lifestyle factors and their mechanisms of action are reviewed, including environmental enrichment and the importance of food intake and some nutrients. Aerobic physical exercise and reduction of chronic stress are also briefly reviewed. It is proposed that lifestyle factors are powerful instruments to promote healthy and successful aging of the brain and delay the appearance of age-related cognitive deficits in elderly people.

scholarly journals Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Camila Gudenschwager ◽  
Isadora Chavez ◽  
Cesar Cardenas ◽  
Christian Gonzalez-Billault
Keyword(s):  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Brain Aging ◽  
Dermal Fibroblasts ◽  
Cellular Reprogramming ◽  
Redox Biology ◽  
Brain Functions ◽  
Age Related ◽  
Human Neurons

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer’s, Parkinson’s, and Huntington’s disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the “aged” context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.

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