Exercise suppresses neuroinflammation for alleviating Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by the emergence of toxic and side effects, and it is an urgent task to explore the underlying mechanisms for the benefits to prevent and treat AD. Herein, based on animal experiments and a few clinical trials, neuroinflammation in AD is characterized by long-term activation of pro-inflammatory microglia and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from the periphery and within the brain continuously activate microglia, thus resulting in a constant source of inflammatory responses. The long-term chronic inflammatory response also exacerbates endoplasmic reticulum oxidative stress in microglia, which triggers microglia-dependent immune responses, ultimately leading to the occurrence and deterioration of AD. In this review, we systematically summarized and sorted out that exercise ameliorates AD by directly and indirectly regulating immune response of the central nervous system and promoting hippocampal neurogenesis to provide a new direction for exploring the neuroinflammation activity in AD.

A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy.

The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross-talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD-related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD-related pathways and is crucial for maintenance of the correct cellular balance by degrading AD-associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD-related signaling pathways, describes key features of these pathways and their cross-talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD.

Emodin inhibits aggregation of amyloid-ß peptide 1-42 and improves cognitive deficits in Alzheimer's disease transgenic mice.

Aggregation of amyloid-ß peptide 1-42 (Aß42) initiates the onset of Alzheimer's disease (AD), and all the drugs designed to attenuate AD have failed in clinical trials. Emodin reduces levels of ß-amyloid, tau aggregation, oxidative stress, and inflammatory response, demonstrating AD therapeutic potential, whereas its effect on the accumulation of the amyloid-ß protein is not well understood. In this work, we investigated emodin activity on Aß aggregation using a range of biochemical, biophysical, and cell-based approaches. We provide evidence to suggest that emodin blocks Aß42 fibrillogenesis and Aß-induced cytotoxicity, displaying a greater effect than that of curcumin. Through adopting three short peptides (Aß1-16, Aß17-33, and Aß28-42), it was proven that emodin interacts with the Leu17-Gly33 sequence. Furthermore, our findings indicated that Val18 and Phe19 in Aß42 are the target residues with which emodin interacts according amino acid mutation experiments. When fed to 8-month-old B6C3-Tg mice for 2 months, high-dose emodin ameliorates cognitive impairment by 60%-70%. Pathological results revealed that levels of Aß deposition in the brains of AD mice treated with a high dose of emodin decreased by 50%-70%. Therefore, our study indicates that emodin may represent a promising drug for AD treatment.

Bone marrow mesenchymal stem cells-derived exosomes reduce Aß deposition and improve cognitive function recovery in mice with Alzheimer's disease by activating sphingosine kinase/sphingosine-1-phosphate signaling pathway.

Exosomes are associated with the development and progression of Alzheimer's disease (AD), although the impact of these extracellular vesicles in brain pathological condition remains incompletely understood. Therefore, this study aimed to investigate the role and mechanism of exosomes signaling in AD. Double transgenic APP/PS1 mice were injected with bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes or combined with SKI-Ⅱ (sphingosine kinase [SphK] inhibitor) or VPC23019 (sphingosine-1-phosphate [S1P] 1 receptor blocker). We observed the spatial learning and memory ability of mice, and assessed the levels of amyloid and proteins. We found that exosomes improved spatial learning and memory ability of APP/PS1 mice, and enhanced the expression of SphK1 and S1P1. Moreover, exosomes inhibited the levels of amyloid and enhanced the expression of NeuN in cortex and hippocampus of APP/PS1 mice. Exosomes repressed the levels of Aß1-40, Aß1-42, BACE1, and PS1, and promoted the expression of neprilysin in APP/PS1 mice. The influence conferred by exosomes was abolished by SKI-Ⅱ or VPC23019. In conclusion, our article confirms that BM-MSCs-derived exosomes reduce Aß deposition and promote cognitive function recovery in AD mice by activating SphK/S1P signaling pathway. Thus, our data suggest that S1P/SphK-containing exosomes should be explored as potential AD cure.

Amyloid-ß plaques may be reduced in advanced stages of cerebral amyloid angiopathy in the elderly.

We examined 29 cases in which cerebral amyloid angiopathy (CAA) was detected among routine aged autopsies. Most cases with severe CAA had many amyloid-ß (Aß) plaques in the occipital cortex. Nonetheless, two cases had few Aß plaques with many small vessels and capillaries with CAA. In the two cases, severe CAA was widely distributed, except in the frontal lobes. Aß deposits in capillaries often showed the characteristic pattern of dysphoric amyloid angiopathy. A few naked plaques were present. Although Aß plaques were sparse near small vessels with CAA, there were many Aß plaques distant from small vessels with CAA. Some of the remaining plaques had a moth-eaten appearance. Based on Aß-positive star-like appearance and results of double immunohistochemistry for glial fibrillary acidic protein and Aß1-42 , some astrocytes appeared to contain Aß. Ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia were scattered within the neuropil, with some present around small vessels with CAA. Iba1-positive microglia also seemed to phagocytose Aß in several senile plaques by double immunostaining. Neurons and neurites identified with a monoclonal antibody against phosphorylated tau (clone AT8) were occasionally detected in sparse plaque areas, with AT8-identified dot-like structures present around capillaries with CAA. Accumulation of T lymphocytes was detected around vessels in the subarachnoid space in one case. The morphological changes detected in our two cases were similar to those of morphological markers of plaque clearance after Aß immunotherapy. Nonetheless, our cases did not receive Aß immunotherapy, but similar pathologies were observed. Overall, advanced CAA cases, including our two cases, may be examples of plaque clearance without Aß immunotherapy. Further studies are needed to resolve the mechanism of Aß plaque clearance using these cases.

Alzheimer's senile plaque as shown by microcryodissection, a new technique for dissociating tissue structures.

Extracellular accumulation of Aß peptides and intracellular aggregation of hyperphosphorylated tau proteins are the two hallmark lesions of Alzheimer disease (AD). The senile plaque is made of a core of extracellular Aß surrounded by phospho-tau positive neurites. It includes multiple components such as axons, synapses, glial fibers and microglia. To visualize the relationships of those elements, an original technique was developed, based on the dilation of interstitial water during freezing. Samples of neocortex, hippocampus and striatum were taken from formalin-fixed brains (one control case; three cases with severe Alzheimer disease). The samples were subjected to various numbers of freezing/thawing cycles (from 0 to 320) with an automated system we devised. The samples were embedded in paraffin, cut and stained with haematoxylin-eosin or immunostained against Aß, phospho-tau, and antigens enriched in axons, synapses, macrophages or astrocytes. Microcryodissection induced the dissociation of tissue components, especially in the grey matter where the neuropil formed an oriented "mesh". The size of the empty spaces separating the fiber bundles and cells increased with the number of cycles. The amyloid core of the senile plaque separated from its neuritic crown at around 300 freezing/thawing cycles. The dissected core remained associated with macrophages containing Aß in their cytoplasm. Phospho-tau positive axons were distinctly seen projecting from the neuritic crown to the isolated amyloid core, where they ended in large synapses. The microcryodissection showed astrocytic processes stuck directly to the core. The original method we developed-microcryodissection-helped understanding how histological components were assembled in the tissue.

Transcranial LED therapy on amyloid-ß toxin 25-35 in the hippocampal region of rats.

Excessive Aß deposition in the brain is associated with the formation of senile plaques, and their diffuse distribution is related to Alzheimer's disease. Thirty rats (EG) were irradiated with light-emitting diode (photobiomodulation (PBM)) in the frontal region of the skull after being inoculated with the Aß toxin in the hippocampus; 30 rats were used as the control group (CG). The analysis was conducted at 7, 14, and 21 days after irradiation. We observed a decreased in Aß deposits in treated animals compared with animals in the CG. The behavioral and motor assessment revealed that the EG group covered a larger ground distance and explored the open field than the CG group on days 14 and 21 (p < 0.05). The EG group was statistically significant in the spatial memory test compared to the CG group on day 14. The use of PBM significantly reduced the presence of Aß plaques and improved spatial memory and behavioral and motor skills in treated animals on day 21.

Gender difference in valproic acid-induced neuroprotective effects on APP/PS1 double transgenic mice modeling Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive impairment with gender difference in specific cognitive ability domains, pathology, and risk of AD. Since valproic acid (VPA) is a widely used mood stabilizer and an antiepileptic drug, which exhibits multiple neuroprotective activities on AD, this study intended to investigate the gender difference in the effect of VPA on APP/PS1 double transgenic mice modeling AD. Behavioral experiments showed that VPA reduced the autonomous behaviors, improved learning and memory, and exhibited gender differences in AD mice compared with the control mice. The decrease in senile plaque, amyloid ß (Aß) 40, and Aß42 caused by VPA in the male AD mice was more notable than that in the female AD mice. Meanwhile, VPA protected brain cells from dying notably in the male AD mice but only slightly in the female AD mice, and VPA treatment thickened the postsynaptic density and markedly increased the number and density of presynaptic vesicles in both male and female AD mice. However, the effects of rescuing early synaptic structural and functional deficits by VPA were more obvious in the male mice. Overall, these results supported the hypothesis that gender difference significantly influences AD and indicated that VPA may be a promising remedy for AD if basic biological differences and gender specificity were prudently taken into account.

Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT†R406W mutation presenting with a broad distribution of abundant senile plaques.

We report the autopsy results of a patient with familial dementia who was diagnosed as having frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with an R406W mutation in the microtubule-associated protein tau (MAPT) gene. This patient showed Alzheimer's disease (AD)-like clinical manifestations from the age of 59, with reduced ß-amyloid1-42 (Aß42 ) and elevated total and phosphorylated tau levels in the cerebrospinal fluid. He did not present with any apparent parkinsonism throughout the disease course. His autopsy at age 73 showed atrophy and neurodegeneration in many brain regions, particularly in the antero-medial temporal cortex and hippocampus, followed by the frontal lobes, with abundant neurofibrillary tangles. In addition, a diffuse distribution of Aß-positive senile plaques, including many neuritic plaques, was observed and classified as stage C according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. These results suggest that analyzing of the MAPT gene is essential for diagnosing familial dementia, even if amyloid markers such as Aß42 in the cerebrospinal fluid and amyloid imaging are positive, or if neuropathological findings indicate a diagnosis of AD.

Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation.

Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD.

Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains.

We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer's disease (AD) patients. Therefore, we tried to determine the cellular component-dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up-regulated around senile plaques, ß-amyloid deposition might be associated with astrocytosis through the HGF signaling pathway.

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease.

Glycosylation is the most common form of post-translational modification in the brain. Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer's disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate-associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of O- and N-linked glycans in autopsy-confirmed AD post-mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell-to-cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both N- and O-linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater N-sialylation of the Aß plaque microenvironment compared with O-sialylation. Plaque-associated microglia displayed the most intense N-sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of N- and O-sialylation between cored and diffuse Aß plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in N-sialylation and no influence of O-sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.

Aß-Aggregation-Generated Blue Autofluorescence Illuminates Senile Plaques as well as Complex Blood and Vascular Pathologies in Alzheimer's Disease.

Senile plaque blue autofluorescence was discovered around 40 years ago, however, its impact on Alzheimer's disease (AD) pathology has not been fully examined. We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aß aggregation in vitro. In DAPI or Hoechst staining, the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque autofluorescence. The flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted. Both Aß self-oligomers and Aß/hemoglobin heterocomplexes generated blue autofluorescence. The Aß amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation, hemolysis, cerebral amyloid angiopathy, vascular plaques, vascular adhesions, and microaneurysms. In summary, we conclude that Aß-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer's disease.

Neurodegenerative lesions: seeding and spreading.

Accumulation of specific proteins has replaced loss of specific populations of neurons in the definition of most neurodegenerative diseases. In some cases, the amino-acid sequence of the protein that accumulates is altered by a mutation in the gene that codes for it but most generally, the primary structure is normal. Much evidence from human neuropathology has been collected over the years indicating that the progression of the lesions in such neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy follow the neuroanatomical connections. More recently, injection of aggregates of the specific proteins in the brain of experimental animals has been attempted in various experimental settings. Brain homogenates containing Aß aggregates induce the early development of Aß deposits in APP transgenic mice. Brain homogenates from various human tauopathies induce tau aggregates in transgenic mice expressing normal human tau. Finally, synthetic preformed fibrils of alpha-synuclein initiate the development of alpha-synuclein accumulation resembling Parkinson's disease in wild-type mice. Experiments in cell cultures suggest that the protein has to be in some specific state of oligomerization or fibrillation to be endocytosed and transported by the neuron. These data suggest that the protein that accumulates in a specific disease is initially misfolded and that this misfolding contaminates normal protein in a prion-like manner - in some cases through the neuronal connections.

The senile plaque: Morphological differences in APP knock-in mice brains by fixatives.

The morphology of senile plaques depends on the APP knock-in mice brain fixative. Solid forms of senile plaques were detected in APP knock-in mice after formic acid treatment with Davidson's and Bouin's fluid fixative as the brain of AD patients. Aß42 was deposited as cored plaques and Aß38 accumulated around Aß42.

Terahertz Irradiation Improves Cognitive Impairments and Attenuates Alzheimer's Neuropathology in the APPSWE/PS1DE9 Mouse: A Novel Therapeutic Intervention for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-ß (Aß), neurofibrillary tangles, neuroinflammation, and neurodegeneration in the brain. In recent years, considering the unsatisfied benefits of pharmacological therapies, non-pharmacological therapy has become a research hotspot for AD intervention. Terahertz (THz) waves with a range between microwave and infrared regions in the electromagnetic spectrum and high permeability to a wide range of materials have great potential in the bioengineering field. However, its biological impacts on the central nervous system, under either physiological or pathological conditions, are poorly investigated. In this study, we first measured the 0.14 THz waves penetration across the skull of a C57BL/6 mouse and found the percentage of THz penetration to be ~70%, guaranteeing that THz waves can reach the relevant brain regions. We then exposed the APPSWE/PS1DE9 mouse model of AD to repeated low-frequency THz waves on the head. We demonstrated that THz waves treatment significantly improved the cognitive impairment and alleviated AD neuropathology including Aß deposition and tau hyperphosphorylation in the AD mice. Moreover, THz waves treatment effectively attenuated mitochondrial impairment, neuroinflammation, and neuronal loss in the AD mouse brain. Our findings reveal previously unappreciated beneficial effects of THz waves treatment in AD and suggest that THz waves may have the potential to be used as a novel therapeutic intervention for this devastating disease.

Brain insulin signaling and cognition: Possible links.

Poor cognitive ability is a consequence of a wide variety of neurobehavioral disorders and is a growing health problem, especially among the elderly and patients with diabetes. The precise underlying cause of this complication is not well-defined. However, recent studies have highlighted the possible role of insulin hormone signaling in brain tissue. Insulin is a metabolic peptide integral to whole body energy homeostasis; it does, however, have extrametabolic impacts, such as upon neuronal circuits. Therefore, it has been suggested that insulin signaling may modify cognitive ability by yet unknown pathways. In the current review, we discuss the cognitive role of brain insulin signaling and consider the possible links between brain insulin signaling and cognitive ability.

Senile plaques in Alzheimer's disease arise from Aß- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Senile plaques are a pathological hallmark of Alzheimer's disease (AD), yet the mechanism underlying their generation remains unknown. Beta-amyloid peptide (Aß) is a major component of senile plaques. We analysed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood Aß contribution to senile plaque development. We found little neural marker co-expression with plaque Aß, while co-expression of blood markers, such as Haemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co-localizing with a characteristic of Hoechst staining-independent blue autofluorescence. Erythrocyte-interacting Aß is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular haemolysis, atherosclerosis, cerebral amyloid angiopathy, microaneurysm, and often with Cathepsin D co-expression. We identified microaneurysms as major sites of amyloid formation. Our data suggest that senile plaques arise from Aß- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

Visualization of Amyloid Oligomers in the Brain of Patients with Alzheimer's Disease.

In the pathogenesis of Alzheimer's disease (AD), highly neurotoxic amyloid-ß (Aß) oligomers appear early, they are thus considered to be deeply involved in the onset of Alzheimer's disease. However, Aß oligomer visualization is challenging in human tissues due to their multiple forms (e.g., low- and high-molecular-weight oligomers, including protofibrils) as well as their tendency to rapidly change forms and aggregate. In this review, we present two visualization approaches for Aß oligomers in tissues: an immunohistochemical (using the monoclonal antibody TxCo1 against toxic Aß oligomer conformers) and imaging mass spectrometry using the small chemical Shiga-Y51 that specifically binds Aß oligomers. TxCo1 immunohistochemistry revealed Aß oligomer distributions in postmortem human brains with AD. Using Shiga-Y51, imaging mass spectrometry revealed Aß oligomer distributions in the brain of a transgenic mouse model for AD. These two methods would potentially contribute to elucidating the pathological mechanisms underlying AD.

Different Aß43 deposition patterns in the brains of aged dogs, sea lions, and cats.

Cerebral amyloid ß (Aß) deposition is a pathological hallmark of Alzheimer's disease (AD). There are several molecular species of Aß, including Aß40, Aß42, and Aß43, and the pathological roles of Aß43 have attracted particular attention in recent years. Aß43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aß42 and Aß40. Aß40 and Aß42 deposition have been demonstrated in several animal species, while Aß43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aß pathologies. In the present study, the deposition patterns of Aß40, Aß42, and Aß43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aß42, Aß43, and Aß40. However, diffuse SPs and capillary CAA lesions were negative for Aß40. In sea lions, all SPs and most CAA lesions were positive for Aß42, Aß43, and Aß40, while capillary CAA lesions were negative for Aß40. In cats, Aß42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aß43, but negative for Aß40. Double-labelling immunohistochemistry revealed the co-localization of Aß42 and Aß43. These findings suggest that Aß43 and Aß42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aß pathology.