Basic Science and Pathogenesis.

Background: Clinicopathological studies suggest a role of minor cerebrovascular changes in the cognitive decline of individuals with a low neurodegenerative burden. However, it remains unclear whether small vascular brain lesions can impact cognition in middle aging individuals. Additionally, recent clinicopathological studies have shown that even a low Alzheimer's disease (AD) neuropathological burden can significantly impact neuropsychiatric function.

Basic Science and Pathogenesis.

Background: Systemic Arterial Hypertension (SAH), distinguished by a persistent elevation of blood pressure, emerges as a risk factor for stroke and Alzheimer's Disease (AD). Additionally, recent evidence suggests that stroke may adversely affect memory, potentially playing a role in the development of AD. This study aimed to investigate the influence of permanent focal ischemic stroke on memory, as well as on sensorimotor function (asymmetry of the front paws) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR), compared to normotensive Wistar Kyoto (WKY) rats.

Basic Science and Pathogenesis.

Background: Apolipoprotein E (ApoE) exhibits isoform-specific interactions with Alzheimer's disease (AD)-related pathology. In comparison with the more common ApoE3 isoform, ApoE4 promotes amyloid-β (Aβ) deposition, enhances tau-mediated neurodegeneration and inflammation. However, the lack of appropriate preclinical models has limited the ability to evaluate the potential synergistic effect of Aβ, tau and ApoE on cognition and disease progression.

Basic Science and Pathogenesis.

Background: Individuals meeting neuropathological criteria for Alzheimer's disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1.

Basic Science and Pathogenesis.

Background: The study of dementia and its differences between the sexes is widely investigated, mainly in Alzheimer's disease. However, most studies on dementia are not carried out in a multiethnic population. Here we analyze demographic data, clinical symptoms, and neuropathological characteristics of a large mixed Brazilian sample.

Basic Science and Pathogenesis.

Background: The molecular mechanisms associated with Alzheimer's Disease (AD) have been extensively studied in mouse models (Mus musculus). However, experimental research in these models is costly and time-consuming. In this context, the nematode Caenorhabditis elegans (C.

Basic Science and Pathogenesis.

Background: Vascular cognitive impairment/dementia (VD) is the second most prevalent cause of dementia following Alzheimer's disease (AD). VD is characterized by the progression of white matter hyperintensity burden (WMH) and associated neurodegeneration. GFAP, a biomarker for reactive astrogliosis, is associated with Aβ pathology and mediates tau-pathology in preclinical AD.

Basic Science and Pathogenesis.

Background: Most research initiatives have emerged from high-income countries (HIC), leaving a gap in understanding the disease's genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC's unique genetics and socioeconomic factors to identify specific Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.

Method: We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort's unique genetic architecture.

Basic Science and Pathogenesis.

Background: Ischemic stroke (IS) is a risk factor for developing Alzheimer's disease (AD). In this context, microglial activation is a shared cellular response to these two conditions that can be either beneficial or detrimental. Previous research has established that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) treatment leads to enhanced functional recovery and reduced brain infarct volume in animal IS models.

Basic Science and Pathogenesis.

Background: Age-related decrease glucose utilization, coupled with insulin resistance, are key features of AD, resulting in reduced glucose utilization/catabolism and oxidative stress generation. Irisin, an exercise-induced hormone promoting mitochondrial biogenesis in adipocytes via PGC-1α, stimulates thermogenic pathways, increases energy expenditure and induces browning of adipose tissue. Further, irisin expression was shown to trigger neuroprotection in AD models.

Basic Science and Pathogenesis.

Background: Animal models of amyloidosis have been instrumental in Alzheimer's disease (AD) research since they can resemble pathophysiological features of human AD. Nevertheless, each model is generated through different genetic engineering strategies, resulting in distinct phenotypes. In this context, whether AD core molecular programs are conserved among mouse models remains to be addressed.

Basic Science and Pathogenesis.

Background: Nitric oxide (NO) is involved in synaptic transmission and cerebral plasticity, playing a role in the memory process. However, in states of brain inflammation, hypoxia, or ischemia, there is induction of inducible nitric oxide synthase (iNOS) expression by astrocytes and pyramidal cells in the brain. Under conditions of chronic activation, there is a decoupling of iNOS dimers, leading to a massive generation of superoxide anion and peroxynitrite, O2.

Basic Science and Pathogenesis.

Background: Clusterin is a major cholesterol transporter in the central nervous system (CNS) and different SNPs in the CLU gene have been associated with Alzheimer's disease (AD) risk. The rs11136000_T variant in the CLU gene has been shown to decrease the risk of AD. In this work, we investigate the role of the CLU rs11136000_T protective variant and of the clusterin protein throughout different phases of the AD spectrum.

Basic Science and Pathogenesis.

Background: The apolipoprotein ε4 (ApoE4) allele is a major risk factor for sporadic Alzheimer's disease (AD) and was shown to promote amyloid-β (Aβ) accumulation and mediate pathophysiological processes in AD. Although the molecular interaction between Aβ and ApoE is acknowledged, the precise nature of this interaction remains unclear. This study aims to explore the biophysical and biochemical nature of the interaction between Aβ and ApoE in the ε3 and ε4 isoforms.

Basic Science and Pathogenesis.

Background: Recent research has demonstrated that the consumption of high fat diet (HFD) can lead to metabolic dysfunctions and cognitive impairments in both mice models and humans. Given the potential negative effects of HFD, it is crucial to explore non-pharmacological alternatives that can serve as a potential treatment for both metabolic dysfunctions and behavioral effects induced by HFD. Therefore, the aim of this study is to assess the impact of chronic and intermittent exposure to cold temperature on the metabolic and cognitive changes associated with HFD consumption.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease(AD) patients experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus(SCN), which is spatially well-conserved but a tiny nucleus in the hypothalamus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression.

Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD) the fact that neuropsychiatric symptoms can predate the onset of cognitive symptoms suggests that greater focus on the non-cognitive behavioral changes in earlier life could be an opportunity to investigate 'latent' mild behavioral impairment (MBI) as a possible diagnostic strategy for preclinical AD.

Method: We used 1- and 6-month-old 3xTg-AD male mice and age-matched wild-type animals (CEUA-ICB/USP: 127/2015). Two batteries of behavioral tests were performed: (1) open field test (OFT), novel object recognition test (NORT), and rotarod test; (2) elevated zero maze test (EZMT), forced swim test (FST), and sucrose preference test (SPT).

Basic Science and Pathogenesis.

Background: Physical exercise has been proposed as an approach to reduce the risk of Alzheimer's disease (AD). Engaging in physical exercise triggers the shedding of the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5), producing a circulating peptide (irisin) that promotes neuroprotection in AD mouse models. Despite recent evidence indicating that reduced FNDC5/irisin levels in brain and cerebrospinal fluid correlate with amyloid beta pathology, the impact of FNDC5/irisin on tau pathology remains uncertain.

Basic Science and Pathogenesis.

Background: Calcineurin, a protein involved in functions such as synaptic plasticity and neuronal survival, plays an important role in the pathophysiology of Alzheimer's disease. This study, randomized, investigated the effects of FK506 (FK), a calcineurin inhibitor, on the behavioral, histological, and biochemical alterations observed in models of neurotoxicity induced by NMDA or Aβ and in a transgenic model for AD, in addition to the organotypic culture model stimulated with NMDA.

Methods: This study involved models for AD to experiment injecting NMDA or Aβ1-42 into the hippocampus of male C57Bl/6 mice aged 8-12 weeks to induce a neurotoxicity model, treating double-transgenic APP/PS1 mice, expressing both mouse/human APP and mutant human PS1, with chronic FK506 for AD, in which, to enable NMDA or Aβ1-42 microinjections, another experiment including a stereotaxic surgery was performed on the C57Bl/6 mice.

Basic Science and Pathogenesis.

Background: Previous studies suggest an association between Alzheimer's disease and carotid artery atherosclerosis. However, the association between atherosclerotic carotid plaque composition and Alzheimer's disease pathology (neuritic plaques and neurofibrillary tangles) has not been explored yet.

Method: Carotid arteries were dissected and the segments with the largest obstruction in the carotid bifurcation, and the common and internal carotid arteries were obtained.

Basic Science and Pathogenesis.

Background: Worldwide, the actual number of 55 million people diagnosed with dementia is estimated to increase to 139 million people affected by dementia in 2050. 61% of these individuals resided in low and middle-income countries (LMIC). Genetic risk factors account for up to 80% of the attributable risk of Alzheimer's disease (AD), the leading cause of dementia.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) features stereotypical spread of hyperphosphorylated tau (p-tau) and beta-amyloid. Although other pathological tau posttranslational modifications (PTMs) have been described in AD, a prevalent disease model preconizes that other tau PTMs always coincide with p-tau, making the latter an excellent marker of pathological tau burden. We showed in experimental studies that truncated tau (tr-tau), a pathological tau PTM generated via cleavage by active caspases, is as common as p-tau in neurons at late AD stages; however, only about 40% of tr-tau positive neurons also show p-tau positivity.

Basic Science and Pathogenesis.

Background: Aging is a natural, irreversible process that can be successful or pathological, resulting in chronic degenerative diseases such as Alzheimer's disease. Low levels of estrogen characterize menopause. Research reveals that the lack of these hormones may be related to dementia and that vitamin D (vit D), when supplemented, has a neuroprotective and neuromodulator effect.

Basic Science and Pathogenesis.

Background: Replacement, Reduction, and Refinement (3R) guidelines propose the use of alternative models to study human diseases. These models have high homology and are less onerous compared to rodents, which dominate Alzheimer's disease (AD) research. However, it is still necessary to investigate whether evolutionary components are conserved among AD models cross-species.

Basic Science and Pathogenesis.

Background: Individuals with early stages of cognitive decline face a significant stagnation in their financial capacity, leading to a decrease in quality of life. However, whether changes in brain function are associated with financial capacity remains unclear. Here, we evaluate the association between financial capacity and brain glucose metabolism.