Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAß-KI) mice.

INTRODUCTION: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome. METHODS: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAß-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD). RESULTS: Eighteen-month female (but not male) hAß-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAß-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups. DISCUSSION: These findings highlight a sex-dependent variation in the microbiomes of hAß-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD. HIGHLIGHTS: Microbial diversity and the abundance of several species differed in human amyloid beta knock-in (hAß-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAß-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

Cross-species comparative hippocampal transcriptomics in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-ß (hAß)-KI, have been developed to better resemble sporadic human AD. METHODS: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAß-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. RESULTS: The three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Experimental validation of consistently dysregulated genes revealed five altered in mice (SLC11A1, S100A6, CD14, CD33, and C1QB) and three in humans (S100A6, SLC11A1, and KCNK). Finally, we identified 17 transcription factors potentially acting as master regulators of AD. CONCLUSION: Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hAß-KI being the more specific one.

A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques.

BACKGROUND: The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2R47H NSS (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. METHODS: Trem2R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain's response to plaques. RESULTS: Trem2R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2R47H NSS (5xFAD/Trem2R47H NSS) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/Trem2R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2R47H NSS mice also display LTP deficits and postsynaptic loss. CONCLUSIONS: The Trem2R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.

Longitudinal Analysis of the Microbiome and Metabolome in the 5xfAD Mouse Model of Alzheimer's Disease.

Recent reports implicate gut microbiome dysbiosis in the onset and progression of Alzheimer's disease (AD), yet studies involving model animals overwhelmingly omit the microbial perspective. Here, we evaluate longitudinal microbiomes and metabolomes from a popular transgenic mouse model for familial AD (5xfAD). Cecal and fecal samples from 5xfAD and wild-type B6J (WT) mice from 4 to 18 months of age were subjected to shotgun Illumina sequencing. Metabolomics was performed on plasma and feces from a subset of the same animals. Significant genotype, sex, age, and cage-specific differences were observed in the microbiome, with the variance explained by genotype at 4 and 18 months of age rising from 0.9 to 9% and 0.3 to 8% for the cecal and fecal samples, respectively. Bacteria at significantly higher abundances in AD mice include multiple Alistipes spp., two Ligilactobacillus spp., and Lactobacillus sp. P38, while multiple species of Turicibacter, Lactobacillus johnsonii, and Romboutsia ilealis were less abundant. Turicibacter is similarly depleted in people with AD, and members of this genus both consume and induce the production of gut-derived serotonin. Contradicting previous findings in humans, serotonin is significantly more concentrated in the blood of older 5xfAD animals compared to their WT littermates. 5xfAD animals exhibited significantly lower plasma concentrations of carnosine and the lysophospholipid lysoPC a C18:1. Correlations between the microbiome and metabolome were also explored. Taken together, these findings strengthen the link between Turicibacter abundance and AD, provide a basis for further microbiome studies of murine models for AD, and suggest that greater control over animal model microbiomes is needed in AD research. IMPORTANCE Microorganisms residing within the gastrointestinal tract are implicated in the onset and progression of Alzheimer's disease (AD) through the mediation of inflammation, exchange of small-molecules across the blood-brain barrier, and stimulation of the vagus nerve. Unfortunately, most animal models for AD are housed under conditions that do not reflect real-world human microbial exposure and do not sufficiently account for (or meaningfully consider) variations in the microbiome. An improved understanding of AD model animal microbiomes will increase model efficacy and the translatability of research findings into humans. Here, we present the characterization of the microbiome and metabolome of the 5xfAD mouse model, which is one of the most common animal models for familial AD. The manuscript highlights the importance of considering the microbiome in study design and aims to lay the groundwork for future studies involving mouse models for AD.

SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aß and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.

Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer's disease.

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimer's disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6 J strain background, across its lifespan - including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, Aß biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the MODEL-AD Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.

Generation of a humanized Aß expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules.

Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer's Disease.

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimer's disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in long-term potentiation followed by quantification of amyloid beta (Aß) plaque burden and neurofibrillary tau tangles, biochemical levels of Aß and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline and show plasma NfL is strongly driven by plaque burden. The results from these analyses are freely available via the AD Knowledge Portal (https://modeladexplorer.org/). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD.

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide.

miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer's disease.

MicroRNAs play a pivotal role in rapid, dynamic, and spatiotemporal modulation of synaptic functions. Among them, recent emerging evidence highlights that microRNA-181a (miR-181a) is particularly abundant in hippocampal neurons and controls the expression of key plasticity-related proteins at synapses. We have previously demonstrated that miR-181a was upregulated in the hippocampus of a mouse model of Alzheimer's disease (AD) and correlated with reduced levels of plasticity-related proteins. Here, we further investigated the underlying mechanisms by which miR-181a negatively modulated synaptic plasticity and memory. In primary hippocampal cultures, we found that an activity-dependent upregulation of the microRNA-regulating protein, translin, correlated with reduction of miR-181a upon chemical long-term potentiation (cLTP), which induced upregulation of GluA2, a predicted target for miR-181a, and other plasticity-related proteins. Additionally, Aß treatment inhibited cLTP-dependent induction of translin and subsequent reduction of miR-181a, and cotreatment with miR-181a antagomir effectively reversed the effects elicited by Aß but did not rescue translin levels, suggesting that the activity-dependent upregulation of translin was upstream of miR-181a. In mice, a learning episode markedly decreased miR-181a in the hippocampus and raised the protein levels of GluA2. Lastly, we observed that inhibition of miR-181a alleviated memory deficits and increased GluA2 and GluA1 levels, without restoring translin, in the 3xTg-AD model. Taken together, our results indicate that miR-181a is a major negative regulator of the cellular events that underlie synaptic plasticity and memory through AMPA receptors, and importantly, Aß disrupts this process by suppressing translin and leads to synaptic dysfunction and memory impairments in AD.

Intra- and extracellular ß-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus.

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as ß-amyloid (Aß) can vary in size, configuration and cellular location, challenging data interpretation in causation studies. Here we present data obtained using adeno-associated viral (AAV) constructs that drive the expression of oligomeric Aß either intra or extracellularly. We observed that expression of Aß in both cellular compartments affect learning and memory, reduce the number of synapses and the expression of synaptic-related proteins, and disrupt chemical long-term potentiation (cLTP). Together, these findings indicate that during the progression AD the early accumulation of Aß inside neurons is sufficient to promote morphological and functional cellular toxicity, a phenomenon that can be exacerbated by the buildup of Aß in the brain parenchyma. Moreover, our AAV constructs represent a valuable tool in the investigation of the pathological properties of Aß oligomers both in vivo and in vitro.

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling.

Defects in interleukin-1ß (IL-1ß)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1ß inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1ß receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

Astrocytes: From the Physiology to the Disease.

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single-synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aß and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aß immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aß immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.

Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease.

Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy.

Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.

Características das pessoas com acidente vascular encefálico atendidas em um centro de referência estadual / Características de las personas con accidente cerebrovascular atendidas em um centro de rehabilitación / Characteristics of encephalic vascular accident patients treated at a state reference center

Encephalic Vascular Accident is a clinical sign of brain dysfunction and it might result in permanent and irreversible lesions. Objective: defined the characteristics such as age, sex and date of the first treatment at a Santa Catarina State’s Rehabilitation Center. Methods: This is a quantitative cross-sectional descriptive study.The Ethnics in Human Research (CEPSH), the Pro Rector for Research and Extension Federal University of Santa Catarina, number 1024 reviewed this study. Results: Stroke affected 25,11% of women between 71-80 years old and 34,09% of the men aged between 61-70 years old. The most common consequence due to stroke was hemiplegia and the study observed that many patients only looked for proper treatment after several years post stroke. Conclusions: The physical therapy is important, so patients can relearn daily tasks and furthermore reintegrate their social life.

Acidente Vascular Encefálico (AVE) é uma disfunção cerebral que causa lesões permanentes e irreversíveis. Objetivo: Avaliar as idades, os sexos e a data do primeiro atendimento das pessoas com AVE atendidas no centro de reabilitação do Estado de Santa Catarina. Métodos: É um estudo quantitativo, descritivo e transversal, sendo a coleta de dados realizada com base documental nos prontuários. O presente estudo foi avaliado pelo Comitê de Ética em Pesquisa com Seres Humanos (CEPSH), Reitoria de Pesquisa e Extensão da Universidade Federal de Santa Catarina de número 1024. Resultados: O AVE afeta 25,11% de mulheres entre 71-80 anos e 34,09% de homens entre 61-70 anos. Observou-se que a sequela mais comum é a hemiplegia e que muitos somente procuravam tratamento após muitos anos de sequelas. Conclusão: Os dados encontrados mostram a importância da terapia física para que os pacientes reaprendam tarefas diárias e auxilia na reintegração social.

El Accidente Cerebrovascular (ACV) es un signo clínico de disfunción cerebral e ocasiona lesiones cerebrales permanentes e irreversibles. Objetivo: Evaluar las edades, sexos y la fecha del tratamiento inicial de los pacientes con accidente cerebrovascular tratados en el centro de rehabilitación en el estado de Santa Catarina. Métodos: El estudio cuantitativo, descriptivo y transversal. Este estudio fue revisado por el Pro Rector de Investigación y Extensión de la Universidad Federal de Santa Catarina para la Investigación Humana (CESPH). La recolección de datos se basó en registros documentales de las personas atendidas en el Centro de Rehabilitación del Estado de Santa Catarina, entre 2000-2009. Resultados: El AVC afecta 25.11% de las mujeres de 71-80 años y el 34,09% de los varones de 61-70 años. La hemiplejia es secuela más común. El estudio destaca que muchos pacientes buscan tratamiento sólo después de muchos años de secuela. Conclusión: Nuestros datos muestran la importancia de la terapia física, ya que permite que los pacientes pueden volver a aprender las tareas cotidianas.

Synaptic Impairment in Alzheimer's Disease: A Dysregulated Symphony.

Alzheimer's disease (AD) is characterized by memory loss, cognitive decline, and devastating neurodegeneration, not only as a result of the extracellular accumulation of beta-amyloid peptide (Aß) and intracellular accumulation of tau, but also as a consequence of the dysfunction and loss of synapses. Although significant advances have been made in our understanding of the relationship of the pathological role of Aß and tau in synapse dysfunction, several questions remain as to how Aß and tau interdependently cause impairments in synaptic function in AD. Overall, more insight into these questions should enable researchers in this field to develop novel therapeutic targets to mitigate or delay the cognitive deficits associated with this devastating disease.