Basic Science and Pathogenesis.

Background: Mitochondrial bioenergetics are essential for cellular function, specifically the intricacies of the electron transport chain (ETC), with Complex IV playing a crucial role in unraveling the mechanisms governing energy production. Mathematical models offer a valuable approach to simulate these complex processes, providing insights into normal mitochondrial function and aberrations associated with various diseases, including neurodegenerative disorders. Our research focuses on introducing and refining a mathematical model, emphasizing Complex IV in the ETC, with objectives including incorporating mitochondrial activity modulation using inhibiting and uncoupling reagents, akin to oxygen consumption experiments.

Basic Science and Pathogenesis.

Background: A growing body of research has focused on inflammation as both a potential biomarker and a risk factor for Alzheimer's disease (AD). The cytokine Interleukin-6 (IL-6) is involved in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. AD has been associated with increased IL-6 expression in brain, however, increased levels of IL-6 have also been linked to conditions such as diabetes and hypertension.

Basic Science and Pathogenesis.

Background: Genetic variants that confer protection from Alzheimer's disease (AD) may be particularly critical in developing therapeutics. To target protective variant identification, we performed genetic association testing among selected individuals with whole genome sequencing (WGS) that remained alive and dementia-free beyond age 85 ("Wellderly").

Methods: We selected 1,873 White and Black Wellderly individuals with documented normal cognition beyond age 85 as determined by direct, in-person assessment with WGS from the NHLBI TOPMed project.

Basic Science and Pathogenesis.

Background: The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models.

Method: We used primary hippocampal cultures, amyloid-β oligomers (AβO)-injected or transgenic animal models, and human brain tissue to determine brain proteasome function and subcellular localization.

Basic Science and Pathogenesis.

Background: White matter hyperintensities (WMHs) are increasingly recognized for their role in cognitive decline and the progression of neurodegenerative conditions including Alzheimer's disease (AD). Despite advances in imaging technologies, the exact contribution of WMHs to disease processes remains a subject of ongoing research. This study aims to apply machine learning approaches to determine critical features of AD-related neuropathologies in vivo.

Basic Science and Pathogenesis.

Background: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022).

Basic Science and Pathogenesis.

Background: Inflammation is central to Alzheimer Disease (AD), as astrocyte reactivity accompanies the appearance of Aβ and phosphorylated tau (Bellaver et al., 2023). As expected, therefore, AD patients have elevated levels of CSF inflammatory cytokines (Onyango et al.

Basic Science and Pathogenesis.

Background: An imbalance between the production and clearance of amyloid beta (Aß) has emerged as a major cause of sporadic Alzheimer's disease (AD). Retinal wholemount studies can identify cell-specific involvement in Aß clearance mechanisms which cannot be accomplished in the brain ex vivo.

Methods: Eye cross-sections of double transgenic (Tg, APP-PS1) and non-carrier sibling female mice (n = 16, 4 per group) at 3- and 9- month ages were probed with antibodies 6E10 (Aβ1-16 amino-acid residues, soluble and insoluble species), ionized calcium-binding adapter molecule 1 (IBA1, microglia/macrophage), glial fibrillary acidic protein (GFAP, astrocytes), glutamine synthetase (GS, Müller cells) and aquaporin-4 (AQP4, membrane water channel) using immunofluorescence.

Basic Science and Pathogenesis.

Background: Ambroxol is an expectorant under study as a treatment for synucleinopathies, such as Parkinson's disease. It is a pharmacological chaperone of the lysosomal enzyme β-glucocerebrosidase (GCase), increasing this enzyme and subsequently reducing accumulation of alpha-synuclein. Although the mechanism of enhanced clearance is not fully understood, ambroxol stimulates lysosomal function through activation of transcription factor EB (TFEB), which drives hundreds of lysosomal genes.

Basic Science and Pathogenesis.

Background: Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain.

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: 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: 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: ApoE4 is the strongest genetic risk factor for late onset Alzheimer's Disease (AD). However, ApoE4 has also been suggested to exhibit antagonistic pleiotropy, a phenomenon by which some allelic variations of a gene promote fitness during certain periods of life but may be detrimental in others. Previous work suggests that ApoE4 carriers exhibit superior performance on executive function tasks in early and middle age, while later in life (>70 years) ApoE4 carriers experience greater cognitive decline across multiple domains.

Basic Science and Pathogenesis.

Background: High blood pressure (BP) is one of the twelve modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although high BP is associated with cognitive decline and structural brain changes, less is known about the long-term association between variable BP and cognitive/brain changes. This study was designed to examine the relationship between variable BP and longitudinal cognitive, post-mortem neuropathology, white matter hyperintensity (WMH), gray matter (GM) volume, and white matter (WM) volume change over time.

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: Frontotemporal dementia is the most common form of dementia impacting those under the age of 60. It is estimated that 30% of affected persons have a genetic predisposition to this disease, with mutations in the genes encoding progranulin (GRN), chromosome 9 open reading frame 72(C9orf72), and microtubule associated protein tau (MAPT). Mutations in MAPT were discovered in 1998, yet to date, there have been no therapies or multisite clinical trials available to families.

Efficacy of a hands-free vascular ultrasound probe holder in active and inactive limbs during cycling exercise.

Measurement of blood flow during exercise is crucial for understanding physiological responses and performance outcomes. However, traditional methods are often invasive, costly, or require substantial training, limiting widespread research in this area. This study introduces the innovative use of limb-affixed ultrasound probe holders for vascular imaging during exercise to overcome these challenges.

Basic Science and Pathogenesis.

Background: Large-scale unbiased proteomic profiling studies have identified a cluster of 31 proteins co-expressed with APP, which is termed the matrisome module 42 (M42). M42 is enriched in AD risk genes, including APOE, with mostly secreted proteins that bind heparin, collectively strongly correlate with the burden of brain pathology and cognitive trajectory, and localize to amyloid plaques in AD brain. For these reasons, M42 has been nominated as a novel therapeutic target for enabling drug discovery by our TREAT-AD Center.

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: An explicit molecular level understanding of Alzheimer's Disease (AD) remains elusive. What initiates the disease and why does it progress? Answering these questions will be crucial to the development of much needed new diagnostics and therapeutics. Though the amyloid hypothesis is often debated, recent biologic trial results support a role for Aβ in AD pathogenesis.

Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is a pathological process diagnosed at autopsy, involving deposition of TDP-43 in the medial temporal lobes. The name LATE-NC was recently proposed to represent the pathological process, while "LATE" has been suggested to represent the clinical syndrome. However, there are currently no available criteria to diagnose this syndrome during life, and the clinical phenotype is not well understood.

Basic Science and Pathogenesis.

Background: While individual etiological hypotheses for AD are researched, few large-scale theoretical integrative efforts linking entities involved in these dysfunctions have been attempted. Experimentally, assessing such a global theory is logistically near impossible to achieve as the number of variables is substantial. Alternatively, computational neuroscience allows for the joint study of multiple entities at this scale, the generation of predictions, and their validation with real data.

Basic Science and Pathogenesis.

Background: Altered neuronal timing and synchrony are biomarkers for Alzheimer's disease (AD) and correlate with memory impairments. Electrical stimulation of the fornix, the main fibre bundle connecting the hippocampus to the septum, has emerged as a potential intervention to restore network synchrony and memory performance in human AD and mouse models. However, electrical stimulation is non-specific and may partially explain why fornix stimulation in AD patients has yielded mixed results.