[Electroacupuncture at "Baihui"（GV20） and "Yongquan"（KI1） improves learning-memory ability of APP/PS1 double transgenic mice by regulating endosomal-lysosomal system].

OBJECTIVE: To explore the mechanism of electroacupuncture（EA） in improving learning-memory ability in Alzheimer's disease （AD） mice from the perspective of endosomal-lysosomal system. METHODS: Male APP/PS1 transgenic mice were randomly divided into model group and EA group （n=10 in each group） and 10 male C57BL/6 wild mice were taken as the normal group. EA （1 Hz/50 Hz, 1 mA） was applied at bilateral "Yongquan"（KI1） and acupuncture was applied at "Baihui" （GV20） for 15 min. The mice of the model and normal groups were subjected to restriction with the same method as those of the EA group for 15 min. The treatment was conducted once every other day for 6 weeks. The spatial learning-memory ability （shown by escape latency of place navigation test and the time of crossing the target platform and total swimming distance in the target quadrant in 1 min of spatial probe test ） was detected by Morris water maze test. The immunoactivity of senile plaques （SP） in the hippocampus tissue was detected by immunohistochemistry. The ultrastructural characters of hippocampal neurons were observed by transmission electron microscope, and the expression levels of Ras-related protein 5 （Rab5）, Ras-related protein 7 （Rab7） and cathepsin D （CTSD） in the hippocampus were detected by Western blot, separately. RESULTS: Compared with the normal group, the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD were significantly increased （P<0.05, P<0.01）, while the number of crossing the original platform and the total swimming distance in the platform quadrant were considerably reduced （P<0.05） in the model group. In contrast to the model group, the EA group had a marked decrease in the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD （P<0.05, P<0.01）, and a striking increase in the number of crossing the original platform and the swimming distance in the platform quadrant （P<0.05）. Results of transmission electron microscope showed an accumulation of endosome, lysosome, and endolysosomes in the hippocampal neurons in the model group, which was evidently milder in the EA group. CONCLUSION: EA of GV20 and KI1 can improve the learning-memory ability of AD mice, which may be related to its function in reducing hippocampal Aß deposition and down-regulating endosomal-lysosomal system activity.

Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease.

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

Aducanumab-Hope or Disappointment for Alzheimer's Disease.

In June 2021, the world was informed about a new drug for Alzheimer's disease approved by the FDA. Aducanumab (BIIB037, ADU), being a monoclonal antibody IgG1, is the newest AD treatment. The activity of the drug is targeted towards amyloid ß, which is considered one of the main causes of Alzheimer's disease. Clinical trials have revealed time- and dose-dependent activity towards Aß reduction, as well as cognition improvement. Biogen, the company responsible for conducting research and introducing the drug to the market, presents the drug as a solution to cognitive impairment, but its limitations, costs, and side effects are controversial. The framework of the paper focuses on the mechanism of aducanumab's action along with the positive and negative sides of the therapy. The review presents the basis of the amyloid hypothesis that is the cornerstone of therapy, as well as the latest information about aducanumab, its mechanism of action, and the possibility of the use of the drug.

Atorvastatin's Reduction of Alzheimer's Disease and Possible Alteration of Cognitive Function in Midlife as well as its Treatment.

Over the past 20 years, advances in the field of pathogenesis have inspired researchers to look into novel pharmacological therapeutics that are more focused on the pathophysiological events of the disease (AD). This review article discussed the prior use of statins for the prevention of Alzheimer's disease, which can help prevent the disease. Other drugs, such as memantine and donepezil, are available, but they cannot prevent the onset of AD in middle age. Based on available clinical data, the valuable effects of statins are mediated by alteration of ß-amyloid (Aß) and tau metabolism, genetic and lifestyle risk factors, along with other clinical aspects of AD. These findings suggested that using statins in middle age may help to prevent Alzheimer's disease by modifying genetic and non-genetic risk factors in later stages of life. In the present review, we elaborated upon the modification of risk factors and amyloid metabolism in the development and progression of AD and their modulation through atorvastatin. Future directions in the research and treatment of Alzheimer's disease patients include the use of antisense oligonucleotides (ASO) to change target expression, and researchers discovered decreased markers of oxidative stress in tissues affected by tau pathology in response to RNA interference treatment.

Hypothesis review: Alzheimer's overture guidelines.

National Institute on Aging-Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based on the assumption that ß-amyloid drives the pathogenesis of sAD, and therefore, ß-amyloid pathology is the sine-qua-non condition for the diagnosis of sAD. The neuropathological diagnosis is based on the concurrence of senile plaques (SPs) and neurofibrillary tangles (NFTs) designated as Alzheimer's disease neuropathological changes. However, NFTs develop in the brain decades before the appearance of SPs, and their distribution does not parallel the distribution of SPs. Moreover, NFTs are found in about 85% of individuals at age 65 and around 97% at age 80. SPs occur in 30% at age 65 and 50%-60% at age 80. More than 70 genetic risk factors have been identified in sAD; the encoded proteins modulate cell membranes, synapses, lipid metabolism, and neuroinflammation. Alzheimer's disease (AD) overture provides a new concept and definition of brain aging and sAD for further discussion. AD overture proposes that sAD is: (i) a multifactorial and progressive neurodegenerative biological process, (ii) characterized by the early appearance of 3R + 4Rtau NFTs, (iii) later deposition of ß-amyloid and SPs, (iv) with particular non-overlapped regional distribution of NFTs and SPs, (v) preceded by or occurring in parallel with molecular changes affecting cell membranes, cytoskeleton, synapses, lipid and protein metabolism, energy metabolism, neuroinflammation, cell cycle, astrocytes, microglia, and blood vessels; (vi) accompanied by progressive neuron loss and brain atrophy, (vii) prevalent in human brain aging, and (viii) manifested as pre-clinical AD, and progressing not universally to mild cognitive impairment due to AD, and mild, moderate, and severe AD dementia.

[Morphological characteristics of the brain nervous tissue during aging]. / Morfologicheskaya kharakteristika nervnoi tkani golovnogo mozga pri starenii.

OBJECTIVE: Identification of morphological manifestations and evaluation of morphometric parameters of the nervous tissue in various structures of the human brain during aging. MATERIAL AND METHODS: Autopsy material was obtained from patients whose causes of death were not associated with neurological diseases. Three age groups were studied: young (35-45 years old) (n=10); eldery (75-89 years old) (n=20); centenarians (over 90 years old) (n=10). Quantitative analysis of large neurons in the compact part of the substantia nigra, basal ganglia, layer V of the cortex, and the pyramidal layer of the hippocampus was carried out. In addition, the brain mass, the thickness of the cortex of the precentral gyrus were measured, the glial index was calculated, and the morphological signs of age-related involution of the brain tissue and intracerebral vessels were assessed. RESULTS: In senile and centenarians, compared with young people, there was a progressive reduction in large neurons of layer V of the cortex, basal ganglia, the pyramidal layer of the hippocampus and substantia nigra, a decrease in brain mass and thickness of the cortex of the precentral gyrus, as well as an increase in the glial index. Changes in blood vessels characteristic of aging are described. Also, during aging, signs characteristic of neurodegeneration were found. CONCLUSION: The results of the study confirm that such brain structures as the cortex of the precentral gyrus, the hippocampus, the basal ganglia, and the substantia nigra lose large neurons with age, followed by the development of gliosis. The identified morphological changes characteristic of aging are phenomenologically similar to a certain set of morphological changes in neurodegenerative diseases of late age.

Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by cognitive decline and progressive memory loss. The aim of this review was to update the state of knowledge on the pathophysiological mechanisms, diagnostic methods and therapeutic approach to AD. Currently, the amyloid cascade hypothesis remains the leading theory in the pathophysiology of AD. This hypothesis states that amyloid-ß (Aß) deposition triggers a chemical cascade of events leading to the development of AD dementia. The antemortem diagnosis of AD is still based on clinical parameters. Diagnostic procedures in AD include fluid-based biomarkers such as those present in cerebrospinal fluid and plasma or diagnostic imaging methods. Currently, the therapeutic armory available focuses on symptom control and is based on four pillars: pharmacological treatment where acetylcholinesterase inhibitors stand out; pharmacological treatment under investigation which includes drugs focused on the control of Aß pathology and tau hyperphosphorylation; treatment focusing on risk factors such as diabetes; or nonpharmacological treatments aimed at preventing development of the disease or treating symptoms through occupational therapy or psychological help. AD remains a largely unknown disease. Further research is needed to identify new biomarkers and therapies that can prevent progression of the pathology.

[Comparative analysis of electroacupuncture, metformin and their combination on cognitive function and senile plaques of cerebral cortex and hippocampus in APP/PS1 mice].

OBJECTIVE: To compare the effect of electroacupuncture (EA), metformin and EA plus metformin on the cognitive ability and senile plaques (SPs) in cerebral cortex and hippocampus of Alzheimer's disease (AD) mice, so as to explore a better treatment method for AD. METHODS: Twenty-four male APP/PS1 mice were randomly divided into model, metformin (medication), EA and EA+medication groups, with 6 mice in each group. Other 6 male wild C57 mice were used as the control group. EA (2 Hz, 1.0 mA) was applied to "Baihui" (GV20) and "Shenshu" (BL23) for 15 min, once a day, for 4 weeks, with 1 day's off every week. The mice of the medication group received gavage of metformin (300 mg·kg-1·d-1) once a day for 4 weeks. Morris water maze tests were used to assess the cognitive function of mice. H.E. staining was used to observe the histopathological changes of neurons in the cortex and hippocampus. Immunohistochemical method was used to observe the cerebral cortex and hippocampal SPs. The expression levels of SPs formation-related proteins: ß-site amyloid precursor protein cleaving enzyme 1(ßACE1) and insulin-degrading enzyme (IDE) in the cortex and hippocampus were detected by Western blot. RESULTS: Compared with the control group, the escape latency, number of SPs and the expression of ßACE1 in the cortex and hippocampus were ob-viously increased (P<0.01), and the times of platform quadrant crossing and the expression of IDE protein were markedly decreased in the model group (P<0.01). In comparison with the model group, the escape latency, and the number of SPs and expression of ßACE1 proteins in the cortex and hippocampus in the 3 treatment groups were significantly down-regulated (P<0.01), while the times of platform quadrant crossing, and the expression of IDE protein in both cortex and hippocampus of the three treatment groups were considerably up-regulated (P<0.01). Comparison among the three treatment groups showed that the therapeutic effect of EA+medication was significantly superior to that of medication and simple EA in down-regulating the escape latency, the number of SPs and expression of ßACE1 in the cortex and hippocampus (P<0.01), and in up-regulating the times of the platform quadrant crossing, and expression of IDE protein in both cortex and hippocampus (P<0.01). No significant differences were found between the simple medication and simple EA in all the indexes mentioned above (P>0.05). CONCLUSION: EA, metformin and EA plus metformin can improve cognitive ability and relieve SP formation in cerebral cortex and hippocampus in AD mice, which may be associated with their functions in down-regulating the expression of ßACE1 and up-regulating the expression of IDE. The therapeutic effects of EA plus metformin are apparently better than those of simple EA and simple metformin.

Combined Neuroprotective Strategies Blocked Neurodegeneration and Improved Brain Function in Senescence-Accelerated Mice.

Increase in the quality of life, combined with drug strategies, has been studied as possibilities for improving memory and delaying the onset of neurodegenerative diseases. A previous study published by the group of the authors has shown that microdose lithium and enriched environment can improve memory in both mice and humans. To elucidate this relationship better, this study aimed to evaluate whether the chronic combination of these two strategies could increase healthy aging in Senescence Accelerated Mouse-Prone 8 (SAMP8). Animals were submitted to either one or both of these strategies until the age of 10 months when they were anesthetized and killed and their hippocampus was extracted. The untreated SAMP-8 group exhibited worse memory and reduced neuronal density with greater neurodegeneration and increased amyloid-ß plaque density compared with the control group. Moreover, significant alterations in proteins related to long-term potentiation, such as, synaptophysin and brain-derived neurotrophic factor (BDNF), were observed in this group. The strategies used in the study maintained long-term memory, reduced anxiety, and increased neuroprotection. Both strategies were efficient in reducing neurodegeneration and increasing parameters related to memory maintenance. In many experiments, the combination of the two strategies was more effective in improving healthy aging. This study sheds light on the combination of strategies that choose to improve the quality of life and drugs with low side effects. Moreover, it opens perspectives for a new field of study for healthy aging.

Dipeptidyl peptidase 4 contributes to Alzheimer's disease-like defects in a mouse model and is increased in sporadic Alzheimer's disease brains.

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid ß peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid ß peptide, several N-terminally truncated fragments of amyloid ß peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid ß peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid ß, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid ß peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid ß. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid ß peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid ß peptide and amyloid ß 42-positive plaques and amyloid ß 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid ß peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression.

Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer's Disease.

BACKGROUND: Familial Alzheimer's disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-ß protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-ß in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD. OBJECTIVE: Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred. METHODS: Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method. RESULTS: Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques. CONCLUSION: These data suggest that the co-deposition of aluminum with amyloid-ß precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-ß may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-ß, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.

Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer's disease.

Asparagine endopeptidase (AEP), a newly identified delta-secretase, simultaneously cleaves both APP and Tau, promoting Alzheimer's disease (AD) pathologies. However, its pathological role in AD remains incompletely understood. Here we show that delta-secretase cleaves BACE1, a rate-limiting protease in amyloid-ß (Aß) generation, escalating its enzymatic activity and enhancing senile plaques deposit in AD. Delta-secretase binds BACE1 and cuts it at N294 residue in an age-dependent manner and elevates its protease activity. The cleaved N-terminal motif is active even under neutral pH and associates with senile plaques in human AD brains. Subcellular fractionation reveals that delta-secretase and BACE1 reside in the endo-lysosomes. Interestingly, truncated BACE1 enzymatic domain (1-294) augments delta-secretase enzymatic activity and accelerates Aß production, facilitating AD pathologies and cognitive impairments in APP/PS1 AD mouse model. Uncleavable BACE1 (N294A) inhibits delta-secretase activity and Aß production and decreases AD pathologies in 5XFAD mice, ameliorating cognitive dysfunctions. Hence, delta- and beta- secretases' crosstalk aggravates each other's roles in AD pathogenesis.

Deletion of Dcf1 Reduces Amyloid-ß Aggregation and Mitigates Memory Deficits.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-ß (Aß) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aß aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. OBJECTIVE: Our goal is to investigate the effect of Dcf1 on Aß aggregation and memory deficits in AD development. METHODS: The mouse and Drosophila AD model were used to test the expression and aggregation of Aß, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. RESULTS: Deletion of Dcf1 resulted in decreased Aß42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aß42 AD Drosophila, the expression of Dcf1 in Aß42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aß aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. CONCLUSION: Dcf1 causes Aß-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.

Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer's disease (AD) mouse model and is increased at early stage in sporadic AD brain.

One of the main components of senile plaques in Alzheimer's disease (AD)-affected brain is the Aß peptide species harboring a pyroglutamate at position three pE3-Aß. Several studies indicated that pE3-Aß is toxic, prone to aggregation and serves as a seed of Aß aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aß N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aß and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aß1-40 to yield Aß2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aß-precursor protein (ßAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aß- and Aß1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aß-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aß N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.

Aß Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors.

Alzheimer's disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid ß peptide (Aß) and by an impairment of calcium homeostasis caused by excessive activation of glutamatergic receptors (excitotoxicity). Here, we studied the effects on calcium homeostasis caused by the formation of Aß oligomeric assemblies. We found that Aß oligomers cause a rapid influx of calcium ions (Ca2+) across the cell membrane by rapidly activating extrasynaptic N-methyl-d-aspartate (NMDA) receptors and, to a lower extent, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments with lysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, indicated that these receptors are activated through a change in membrane tension induced by the oligomers and transmitted mechanically to the receptors via the lipid bilayer. Indeed, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects. An increased rotational freedom observed for a fluorescent probe embedded within the membrane in the presence of the oligomers also indicates a membrane stretch. These results reveal a mechanism of toxicity of Aß oligomers in Alzheimer's disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.

Heterogenous deposition of ß-amyloid in the brain of aged dogs.

Dogs have been used as animal models for human diseases in which there is beta-amyloid (Aß) deposition in the central nervous system (CNS), such as Alzheimer's and cerebral amyloid angiopathy (CAA). However, many aspects of Aß deposition in the CNS of dogs still remain unknown. This study aimed to evaluate the deposition of Aß in different areas of the CNS of aged dogs from different breeds. Aß was detected in the brains of aged dogs, forming either senile plaques in the neuropil of cortical gray matter or within the walls of parenchymal or leptomeningeal blood vessels. There was a positive correlation between aging and senile plaques or CAA. In dogs older than 8 years, there was no correlation between the area of Aß plaques and age, with frontal, temporal, and occipital cortices being affected with approximately equal frequency. There was a positive correlation between Aß deposition in vessel walls and age. Importantly, CAA was associated with the occurrence of microperivascular hemorrhages in the brains of aged dogs. In conclusion, this study demonstrated that Aß deposition as plaques or within vessel walls are extremely heterogenous in dogs from different breeds and sizes. Although many features of this disease in dogs are similar to those observed in humans, the choice of dog breed and size as a model for human disease will substantially affect the pattern of Aß deposition.

The Pathogenesis Mechanism, Structure Properties, Potential Drugs and Therapeutic Nanoparticles against the Small Oligomers of Amyloid-ß.

Alzheimer's Disease (AD) is a devastating neurodegenerative disease that affects millions of people in the world. The abnormal aggregation of amyloid ß protein (Aß) is regarded as the key event in AD onset. Meanwhile, the Aß oligomers are believed to be the most toxic species of Aß. Recent studies show that the Aß dimers, which are the smallest form of Aß oligomers, also have the neurotoxicity in the absence of other oligomers in physiological conditions. In this review, we focus on the pathogenesis, structure and potential therapeutic molecules against small Aß oligomers, as well as the nanoparticles (NPs) in the treatment of AD. In this review, we firstly focus on the pathogenic mechanism of Aß oligomers, especially the Aß dimers. The toxicity of Aß dimer or oligomers, which attributes to the interactions with various receptors and the disruption of membrane or intracellular environments, were introduced. Then the structure properties of Aß dimers and oligomers are summarized. Although some structural information such as the secondary structure content is characterized by experimental technologies, detailed structures are still absent. Following that, the small molecules targeting Aß dimers or oligomers are collected; nevertheless, all of these ligands have failed to come into the market due to the rising controversy of the Aß-related "amyloid cascade hypothesis". At last, the recent progress about the nanoparticles as the potential drugs or the drug delivery for the Aß oligomers are present.

The Dynamics of ß-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Neuropathologically, AD is characterized by the deposition of a 39- to 42-amino acid long ß-amyloid (Aß) peptide in the form of senile plaques. Several post-translational modifications (PTMs) in the N-terminal domain have been shown to increase the aggregation and cytotoxicity of Aß, and specific Aß proteoforms (e.g., Aß with isomerized D7 (isoD7-Aß)) are abundant in the senile plaques of AD patients. Animal models are indispensable tools for the study of disease pathogenesis, as well as preclinical testing. In the presented work, the accumulation dynamics of Aß proteoforms in the brain of one of the most widely used amyloid-based mouse models (the 5xFAD line) was monitored. Mass spectrometry (MS) approaches, based on ion mobility separation and the characteristic fragment ion formation, were applied. The results indicated a gradual increase in the Aß fraction of isoD7-Aß, starting from approximately 8% at 7 months to approximately 30% by 23 months of age. Other specific PTMs, in particular, pyroglutamylation, deamidation, and oxidation, as well as phosphorylation, were also monitored. The results for mice of different ages demonstrated that the accumulation of Aß proteoforms correlate with the formation of Aß deposits. Although the mouse model cannot be a complete analogue of the processes occurring in the human brain in AD, and several of the observed parameters differ significantly from human values supposedly due to the limited lifespan of the model animals, this dynamic study provides evidence on at least one of the possible mechanisms that can trigger amyloidosis in AD, i.e., the hypothesis on the relationship between the accumulation of isoD7-Aß and the progression of AD-like pathology.

A potential defense mechanism against amyloid deposition in cerebellum.

Amyloid-ß (Aß) is the major component of senile plaques in Alzheimer's disease (AD) brains. Senile plaques are generally observed in cerebral cortex (CTX) rather than cerebellum (CBL) in AD patients. However, it is not clear why CBL has less Aß deposition than CTX. It is very important to elucidate the mechanism of suppressing Aß deposition in CBL, because it contributes to understanding of not only AD pathogenesis but also prevention and cure of AD. In this study, we explored to figure out the potential mechanism of reducing Aß deposition in CBL. We observed higher age-dependent elevation of Aß level in CTX rather than CBL of human APP knock-in AD model mice, although we detected no significant differences in the levels of interstitial fluid Aß in these brain tissues. These data imply that less Aß deposition in CBL is due to enhanced Aß clearance rather than altered Aß production in CBL. To gain insights into Aß clearance in CBL, we injected fluorescence-labeled Aß in brain tissues. Importantly diffusion area of fluorescent Aß in CBL was roughly six-times larger than that in CTX within 2 h of injection. In addition, injected Aß area in CBL decreased sharply after 24 h and CBL-injected Aß was robustly detected in deep cervical lymph nodes (DcLNs). In contrast, diffusion area of fluorescent Aß in CTX was consistent up to 72 h and CTX-injected Aß was faintly detected in DcLNs. Our data suggest that enhanced Aß drainage in association with meningeal lymphatic system is responsible for less Aß deposition in CBL.

Collagenous Alzheimer amyloid plaque component impacts on the compaction of amyloid-ß plaques.

Massive deposition of amyloid ß peptides (Aß) as senile plaques (SP) characterizes the brain pathology of Alzheimer's disease (AD). SPs exhibit a variety of morphologies, although little is known about the SP components that determine their morphology. Collagenous Alzheimer amyloid plaque component (CLAC) is one of the major non-Aß proteinaceous components of SP amyloid in AD brains. Here we show that overexpression of CLAC precursor (CLAC-P) in the brains of APP transgenic mice results in a significant remodeling of amyloid pathology, i.e., reduction in diffuse-type amyloid plaques and an increase in compact plaques laden with thioflavin S-positive amyloid cores. In vivo microdialysis revealed a significant decrease in Aß in the brain interstitial fluid of CLAC-P/APP double transgenic mice compared with APP transgenic mice. These findings implicate CLAC in the compaction of Aß in amyloid plaques and the brain dynamics of Aß.