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Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration currently approved for AD have shown low effectiveness in delaying the progression of the disease. The focus has shifted to non‐pharmacological interventions (NPIs) because of the challenges associated with pharmacological treatments for AD. One such intervention is environmental enrichment (EE), which has been reported to restore cognitive decline associated with AD effectively. However, the therapeutic mechanisms by which EE improves symptoms associated with AD remain unclear. Therefore, this study aimed to reveal the mechanisms underlying the alleviating effects of EE on AD symptoms using histological, proteomic, and neurotransmitter‐related analyses. Wild‐type (WT) and 5XFAD mice were maintained in standard housing or EE conditions for 4 weeks. First, we confirmed the mitigating effects of EE on cognitive impairment in an AD animal model. Then, histological analysis revealed that EE reduced Aβ accumulation, neuroinflammation, neuronal death, and synaptic loss in the AD brain. Moreover, proteomic analysis by liquid chromatography–tandem mass spectrometry showed that EE enhanced synapse‐ and neurotransmitter‐related networks and upregulated synapse‐ and neurotransmitter‐related proteins in the AD brain. Furthermore, neurotransmitter‐related analyses showed an increase in acetylcholine and serotonin concentrations as well as a decrease in polyamine concentration in the frontal cortex and hippocampus of 5XFAD mice raised under EE conditions. Our findings demonstrate that EE restores cognitive impairment by alleviating AD pathology and regulating synapse‐related proteins and neurotransmitters. Our study provided neurological evidence for the application of NPIs in treating AD. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) deposition and Aβ-induced neurodegeneration appear in the retina and retinorecipient areas in the early stages of Alzheimer's disease (AD). Although these Aβ-related changes in the retina cause damage to the visual functions, no studies have yet revealed the alterations in the visual pathways of AD. Therefore, we investigated the alterations of visual circuits in the AD mouse model using anterograde tracer cholera toxin β subunits (CTβ). Moreover, we investigated the Aβ accumulation in the retina and retinorecipient areas and the neuronal loss, and synaptic degeneration in retinorecipient areas by immunofluorescent staining of 4- and 12-month-old female 5XFAD transgenic mice. Our results demonstrated that Aβ accumulation and neurodegeneration occurred in the retina and retinorecipient regions of early and late stages of the 5XFAD mice. Retinal efferents to the suprachiasmatic nucleus and lateral geniculate nucleus were impaired in the early stage of AD. Moreover, retinal connections to the dorsal lateral geniculate nucleus and superior colliculus were degenerated in the late-stage of AD. These findings reveal the Aβ-related pathology induced visual circuit disturbances at the mesoscale level in both the early and late stages of AD and provide anatomical and functional insights into the visual circuitry of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aβ) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that Platycodon grandiflorum root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aβ accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aβ related pathology and ameliorating Aβ induced cognitive impairment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Biological aging provokes morbidity and several functional declines, causing older adults more susceptible to a variety of diseases than younger adults. In particular, aging is a major risk factor contributing to non-communicable diseases, such as neurodegenerative disorders. Alzheimer's disease (AD) is an aging-related neurodegenerative disease that is characterized by cognitive deficits and the formation of amyloid plaques formed by the accumulation of amyloid-β (Aβ) peptides. Non-saponin fraction with rich polysaccharide (NFP) from red ginseng, the largest fraction of the components of red ginseng, perform many biological activities. However, it has not been clarified whether the NFP from Korean red ginseng (KRG) has beneficial effects in the aging and AD. First, proteomics analysis was performed in aged brain to identify the effect of NFP on protein changes, and we confirmed that NFP induced changes in proteins related to the neuroprotective- and neurogenic-effects. Next, we investigated (1) the effects of NFP on AD pathologies, such as Aβ deposition, neuroinflammation, neurodegeneration, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN), in 5XFAD transgenic mouse model of AD using immunostaining; (2) the effect of NFP on Aβ-mediated mitochondrial respiration deficiency in HT22 mouse hippocampal neuronal cells (HT22) using Seahorse XFp analysis; (3) the effect of NFP on cell proliferation using WST-1 analysis; and (4) the effect of NFP on Aβ-induced cognitive dysfunction in 5XFAD mouse model of AD using Y-maze test. Histological analysis indicated that NFP significantly alleviated the accumulation of Aβ, neuroinflammation, neuronal loss, and mitochondrial dysfunction in the subiculum of 5XFAD mouse model of AD. In addition, NFP treatment ameliorated mitochondrial deficits in Aβ-treated HT22 cells. Moreover, NFP treatment significantly increased the AHN and neuritogenesis of neural stem cells in both healthy and AD brains. Furthermore, NFP significantly increased cell proliferation in the HT22 cells. Finally, NFP administration significantly enhanced and restored the cognitive function of healthy and AD mice, respectively. Taken together, NFP treatment demonstrated changes in proteins involved in central nervous system organization/maintenance in aged brain and ameliorates AD pathology. Collectively, our findings suggest that NFP from KRG could be a potential therapeutic candidate for aging and AD treatments. Image 1 • In aged brain, NFP from KRG shows changes in proteins related to the neuroprotective- and neurogenic-effects. • NFP from KRG exhibits therapeutic efficacy in AD pathology and AD-related cognitive decline. • NFP from KRG shows changes in proteins related in CNS organization/maintenance in aged brain and ameliorates AD pathogenesis. [ABSTRACT FROM AUTHOR]