Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

Download Full-text

Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20123030 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3030 ◽

Cited By ~ 10

Author(s):

Soo Jung Shin ◽

Seong Gak Jeon ◽

Jin-il Kim ◽

Yu-on Jeong ◽

Sujin Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hippocampal Formation ◽

Experimental Models ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Red Ginseng ◽

Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Download Full-text

Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Aβ-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer’s Disease-Related Animal Model

International Journal of Molecular Sciences ◽

10.3390/ijms21113879 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3879

Author(s):

Yong Ho Park ◽

Soo Jung Shin ◽

Hyeon soo Kim ◽

Sang Bum Hong ◽

Sujin Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Docosahexaenoic Acid ◽

Cell Model ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Omega 3 ◽

Ht22 Cells

It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aβ) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aβ in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aβ-overexpressing model. We found that omega-3 PUFAs significantly improved Aβ-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aβ accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.

Download Full-text

Jowiseungchungtang Inhibits Amyloid-β Aggregation and Amyloid-β-Mediated Pathology in 5XFAD Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19124026 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4026 ◽

Cited By ~ 4

Author(s):

Soo Shin ◽

Yu-on Jeong ◽

Seong Jeon ◽

Sujin Kim ◽

Seong-kyung Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Loss ◽

Amyloid Β ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Aβ Aggregation ◽

5Xfad Mice

Alzheimer’s disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-β (Aβ) peptides in the brain is considered to be the major pathology of AD, inhibition of Aβ aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aβ aggregation. Thus, we investigated whether JWS could protect against both Aβ aggregates and Aβ-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer’s disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aβ aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aβ aggregation, Aβ-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aβ aggregation, Aβ-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.

Download Full-text

Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Download Full-text

Does Impairment of Adult Neurogenesis Contribute to Pathophysiology of Alzheimer's Disease? A Still Open Question

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.578211 ◽

2021 ◽

Vol 13 ◽

Author(s):

Domenica Donatella Li Puma ◽

Roberto Piacentini ◽

Claudio Grassi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Adult Neurogenesis ◽

Memory Formation ◽

Hippocampal Neurogenesis ◽

Synaptic Function ◽

Adult Hippocampal Neurogenesis ◽

Amyloid Β Protein

Adult hippocampal neurogenesis is a physiological mechanism contributing to hippocampal memory formation. Several studies associated altered hippocampal neurogenesis with aging and Alzheimer's disease (AD). However, whether amyloid-β protein (Aβ)/tau accumulation impairs adult hippocampal neurogenesis and, consequently, the hippocampal circuitry, involved in memory formation, or altered neurogenesis is an epiphenomenon of AD neuropathology contributing negligibly to the AD phenotype, is, especially in humans, still debated. The detrimental effects of Aβ/tau on synaptic function and neuronal viability have been clearly addressed both in in vitro and in vivo experimental models. Until some years ago, studies carried out on in vitro models investigating the action of Aβ/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions (e.g., different cellular/animal models, different Aβ and/or tau isoforms, concentrations, and/or aggregation profiles). To date, studies investigating in situ adult hippocampal neurogenesis indicate severe impairment in most of transgenic AD mice; this impairment precedes by several months cognitive dysfunction. Using experimental tools, which only became available in the last few years, research in humans indicated that hippocampal neurogenesis is altered in cognitive declined individuals affected by either mild cognitive impairment or AD as well as in normal cognitive elderly with a significant inverse relationship between the number of newly formed neurons and cognitive impairment. However, despite that such information is available, the question whether impaired neurogenesis contributes to AD pathogenesis or is a mere consequence of Aβ/pTau accumulation is not definitively answered. Herein, we attempted to shed light on this complex and very intriguing topic by reviewing relevant literature on impairment of adult neurogenesis in mouse models of AD and in AD patients analyzing the temporal relationship between the occurrence of altered neurogenesis and the appearance of AD hallmarks and cognitive dysfunctions.

Download Full-text

Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

International Journal of Molecular Sciences ◽

10.3390/ijms222313136 ◽

2021 ◽

Vol 22 (23) ◽

pp. 13136

Author(s):

Han Seok Koh ◽

SangJoon Lee ◽

Hyo Jin Lee ◽

Jae-Woong Min ◽

Takeshi Iwatsubo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Treatment Strategies ◽

Tau Pathology ◽

Memory Decline ◽

Tnf Α ◽

The Brain

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

Download Full-text

Resveratrol and Neuroprotection: Impact and Its Therapeutic Potential in Alzheimer's Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.619024 ◽

2020 ◽

Vol 11 ◽

Author(s):

Md. Habibur Rahman ◽

Rokeya Akter ◽

Tanima Bhattacharya ◽

Mohamed M. Abdel-Daim ◽

Saad Alkahtani ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Tau Proteins ◽

Amyloid Peptides ◽

Work Done

Alzheimer’s disease (AD) is a progressive cortex and hippocampal neurodegenerative disease which ultimately causes cognitively impaired decline in patients. The AD pathogen is a very complex process, including aggregation of Aβ (β-amyloid peptides), phosphorylation of tau-proteins, and chronic inflammation. Exactly, resveratrol, a polyphenol present in red wine, and many plants are indicated to show the neuroprotective effect on mechanisms mostly above. Resveratrol plays an important role in promotion of non-amyloidogenic cleavage of the amyloid precursor protein. It also enhances the clearance of amyloid beta-peptides and reduces the damage of neurons. Most experimental research on AD and resveratrol has been performed in many species, both in vitro and in vivo, during the last few years. Nevertheless, resveratrol’s effects are restricted by its bioavailability in the reservoir. Therefore, scientists have tried to improve its efficiency by using different methods. This review focuses on recent work done on the cell and animal cultures and also focuses on the neuroprotective molecular mechanisms of resveratrol. It also discusses about the therapeutic potential onto the treatment of AD.

Download Full-text

Unique Microglial Transcriptomic Signature within the Hippocampal Neurogenic Niche

10.1101/2021.08.29.457876 ◽

2021 ◽

Author(s):

Sana Chintamen ◽

Pallavi Gaur ◽

Nicole Vo ◽

Elizabeth Bradshaw ◽

Vilas Menon ◽

...

Keyword(s):

Gene Signature ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Neurogenic Niche ◽

Expression Of Genes ◽

Transcriptomic Signature ◽

Specialized Population ◽

Lower Expression

Microglia, the resident immune cells of the brain, are crucial in the development of the nervous system. Recent evidence demonstrates that microglia modulate adult hippocampal neurogenesis by inhibiting cell proliferation of neural precursors and survival both in vitro and in vivo, thus maintaining a balance between cell division and cell death in the neural stem cell pool. There are increasing reports suggesting these microglia found in neurogenic niches differ from their counterparts in non-neurogenic areas. Here, we present evidence that microglia in the hippocampal neurogenic niche are a specialized population that express genes known to regulate neurogenesis. By comprehensively profiling myeloid lineage cells in the hippocampus using single cell RNA-sequencing, we resolve transcriptomic differences in microglia originating from the subgranular zone. These cells have lower expression of genes associated with homeostatic microglia and increased expression of genes associated with phagocytosis. Intriguingly, this small yet distinct population expresses a gene signature with substantial overlap with previously characterized phenotypes, including disease associated microglia (DAM), a particularly unique and compelling microglial state.

Download Full-text

Neurotrophin-3 Promotes the Neuronal Differentiation of BMSCs and Improves Cognitive Function in a Rat Model of Alzheimer's Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.629356 ◽

2021 ◽

Vol 15 ◽

Author(s):

Zhongrui Yan ◽

Xianjing Shi ◽

Hui Wang ◽

Cuiping Si ◽

Qian Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Neuronal Differentiation ◽

Molecular Mechanisms ◽

Therapeutic Effects ◽

Model Of Alzheimer’S Disease ◽

Neurotrophin 3

Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has the potential to be developed into an effective treatment for neurodegenerative diseases such as Alzheimer's disease (AD). However, the therapeutic effects of BMSCs are limited by their low neural differentiation rate. We transfected BMSCs with neurotrophin-3 (NT-3), a neurotrophic factor that promotes neuronal differentiation, and investigated the effects of NT-3 gene overexpression on the differentiation of BMSCs into neurons in vitro and in vivo. We further studied the possible molecular mechanisms. We found that overexpression of NT-3 promoted the differentiation of BMSCs into neurons in vitro and in vivo and improved cognitive function in rats with experimental AD. By contrast, silencing NT-3 inhibited the differentiation of BMSCs and decreased cognitive function in rats with AD. The Wnt/β-catenin signaling pathway was involved in the mechanism by which NT-3 gene modification influenced the neuronal differentiation of BMSCs in vitro and in vivo. Our findings support the prospect of using NT-3-transduced BMSCs for the development of novel therapies for AD.

Download Full-text

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

International Journal of Molecular Sciences ◽

10.3390/ijms20184641 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4641 ◽

Cited By ~ 7

Author(s):

Alfonso Gautieri ◽

Marten Beeg ◽

Marco Gobbi ◽

Federica Rigoldi ◽

Laura Colombo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Dynamics ◽

Molecular Mechanisms ◽

Amyloid Fibrils ◽

Neurological Diseases ◽

Fibrillar Structure ◽

Structure Based Drug Design

The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer’s disease.

Download Full-text