Basic Science and Pathogenesis.

Ageing changes the adult brain at the molecular, cellular and functional levels, driving regenerative decline, inflammation, cognitive impairments and susceptibility to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD). There is overwhelming evidence that regular physical exercise can counteract cognitive decline in both healthy ageing and in neurodegenerative conditions such as AD, with exerkines, the circulating humoral factors that are secreted into the blood stream in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear.

Basic Science and Pathogenesis.

Background: Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated on up to 55 epitopes. Emerging studies suggest that phosphorylation of specific epitopes may alter the role of tau. The role of specific pTau species can be explored through protein interaction ("interactome") studies.

Basic Science and Pathogenesis.

Background: Whilst numerous studies have explored the relationship between Alzheimer's disease (AD) and diabetes, there remains significant conflicting evidence as to their relationship. Some studies suggest an increased likelihood of developing AD in individuals with diabetes, especially type 2 diabetes (T2D) and that both diseases share pathological features. In contrast, other studies indicate that T2D is more aligned with vascular cognitive impairment and dementia and associated cerebrovascular/white matter pathology.

Basic Science and Pathogenesis.

Background: Alzheimer's Disease (AD) is the most prevalent form of dementia globally. While some familial cases are observed, sporadic AD cases are more common and reflect a high level of complexity, with individual risk determined by the interaction of polygenic and environmental factors.

Objective: To characterize polygenic genetic risk factors in individuals with cognitive impairment and Alzheimer's Disease across four regions of Peru.

Basic Science and Pathogenesis.

Background: Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer's disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g.

Basic Science and Pathogenesis.

Background: The extracellular amyloid plaques, one of the pathological hallmarks of Alzheimers Disease (AD), are frequently also observed in the cortex of cognitively unimpaired subjects or as co-pathology in other neurodegenerative diseases. Progressive deposition of fibrillar amyloid-β (Aβ) as amyloid plaques for two decades prior disease onset leads to extensive isomerization of Aβ N-terminus. Quantifying the extent of isomerized Aβ can be provide insight into the different stages of amyloidosis in the brain.

Basic Science and Pathogenesis.

Background: A better understanding of the molecular process that drive Alzheimer's disease(AD) are required to develop effective biomarkers and therapies. This includes determining how essential elements like Fe, Cu and Zn are involved in the disease. In the literature there is debate over the role of iron in AD and there are reports of increased, decreased and unchanged levels of Fe in AD brain.

Basic Science and Pathogenesis.

Background: SMOC1 has recently emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). SMOC1 is one of the earliest changing proteins in AD, with SMOC1 cerebrospinal fluid levels increasing 29 years before symptom onset in autosomal dominant AD. Despite this clear association with disease, very little is known about the role of SMOC1 in AD or its function in the brain.

Basic Science and Pathogenesis.

Background: Brain iron dyshomeostasis has been observed in behavioral deficits relevant to neurodegenerative diseases such as Alzheimer's disease (AD), but it remains unclear whether it is a primary cause or an epiphenomenon of disease.

Method: We assessed the effects of brain iron dyshomeostasis on spatial cognition and cognitive flexibility using the IntelliCage system, recognition memory using novel object recognition tasks and anxiety-like behavior using the open field and elevated plus maze tests. We investigated these phenotypes in a HfexTfr2 mouse model of brain iron dyshomeostasis alone (Iron) or combined with an APP/PS1 model of Alzheimer's Aβ amyloidosis (Aβ+Iron), compared with APP/PS1 mice with Aβ amyloidosis alone (Aβ) or wildtype controls.

MYO18B promotes lysosomal exocytosis by facilitating focal adhesion maturation.

Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we revealed that paucimannosidic proteins are produced by lysosomal glycosidases and secreted via lysosomal exocytosis.

Basic Science and Pathogenesis.

Background: UK Biobank data show mutations related to the iron disorder hemochromatosis can approximately double the risk of dementia, in particular clinically diagnosed vascular dementia. Insights into the etiology of this dementia may be provided by cerebrovasculopathy in our new "Aβ+Iron" mouse model, which combines hemochromatosis-related mutations and amyloidosis, with increases in soluble Aβ species and plaques. This was created by crossing an established APP/PS1 model of β-amyloidosis with our reported HfexTfr2 model of hemochromatosis-related mutations exhibiting brain iron dyshomeostasis (Heidari Mol.

Basic Science and Pathogenesis.

Background: The reduced phagocytosis of amyloid β (Aβ) by microglia is linked to increased cognitive decline in Alzheimer's disease (AD) patients. Previous methods utilized anti-Aβ antibodies and flow cytometry to reveal Aβ surface binding without internalization. This study introduces a "Two-Color Fluorescent Reporting System" to overcome limitations, allowing differentiation between intra- and extracellular Aβ.

Cardiovascular effects of tirzepatide.

Tirzepatide is a first-in-class dual agonist at receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) for the treatment of T2D and obesity with unprecedented efficacy for glycaemic control and reductions in body weight as well as improvements in blood pressure and lipid profile compared with placebo and GLP-1 receptor agonists. To date, clinical trials of tirzepatide have fulfilled the requirement by regulatory authorities of demonstrated cardiovascular safety in high-risk patients. Whether cardiovascular benefits will be found with dual GLP-1/GIP receptor agonists remains uncertain, and the contribution of GIP receptor activation to cardiovascular risk has not been established.

Enhancement of wheat straw pellet quality for bioenergy through additive blending.

Densification of biomass through pelletizing offers a promising approach to producing clean biofuels from renewable resources. This study, which investigates the impact of additive blends on wheat straw pellet making and upgrading the physiochemical properties, has revealed exciting possibilities. Five additives, including sawdust (SD), bentonite clay (BC), corn starch (S), crude glycerol (CG), and biochar (BioC), were chosen for this study.

Basic Science and Pathogenesis.

Background: The amyloid cascade hypothesis posits a sequence of events proceeding from amyloid-β (Aβ) deposition to entorhinal cortical (EC) tau to neocortical (meta-temporal) tau. This study examined how genetics may modify relationships between these variables on the AD pathway.

Methods: We used causal path analyses to model effects of sex, APOE-ε4 (0,1,2 alleles), and genetic risk for neuroinflammation on Aβ, EC tau and meta temporal tau.

Basic Science and Pathogenesis.

Background: Mounting evidence support the involvement of adaptive immune system in the pathogenesis of Alzheimer's disease (AD). The current study investigated the age-dependent changes in the abundance of B and T cell subtypes in APP/PS1 mice, a commonly used model for AD.

Method: Peripheral blood was collected through cardiac puncture from 6-, 9-, 12-month-old APP/PS1 transgenic (TG) mice (APPsw and PSEN1dE9, n = 8-12) and their wildtype (WT) littermates (C57BL/6J, n = 12-15).

Basic Science and Pathogenesis.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, hereditary cerebrovascular disease which causes stroke, complex migraine, and cognitive impairment. Given its monogenic nature, CADASIL is considered a 'pure' model of small vessel disease and vascular dementia. CADASIL is caused by NOTCH3 pathogenic variants with a broad resulting phenotypic spectrum.

Basic Science and Pathogenesis.

Background: The cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood.

Basic Science and Pathogenesis.

Background: Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer's disease. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects. Synthetic in vitro-transcribed mRNA encoding antibodies presents a promising alternative to conventional passive immunotherapy and overcomes the need to generate recombinant antibodies.

Basic Science and Pathogenesis.

Background: Our research group is currently exploring the potential of Butyric acid (NaB), a Short Chain Fatty Acid (SCFA), as a novel therapeutic agent for Alzheimer's disease (AD).

Methods: In our investigation using the 5xFAD mouse model of AD, we observed that NaB had significant effects on Aβ levels, as well as on associative learning and cognitive functioning. Notably, we recorded a 40% reduction in brain Aβ and a 25% increase in fear response during both cued and contextual testing.

Basic Science and Pathogenesis.

Background: Subjective Cognitive Complaints (SCCs) can often precede mild cognitive impairment and dementia longitudinally. While increasingly considered an early prodromal stage of dementia, SCCs can also be a symptom of depression. Previous research found that SCCs in the absence of cognitive impairment, controlling for symptoms of depression, were moderately heritable and genetically associated with memory.

Basic Science and Pathogenesis.

Background: Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is categorized as a complicated disorder of extreme fatigue lasting for at least six months without any underlying medical problem and currently has no concrete treatment regimen. This is associated with neurological complications like brain fog, insomnia, psychiatric disturbances and above all neuroinflammation. A chronic forced swim test model of CFS has been established since more than a decade at our laboratory.

Basic Science and Pathogenesis.

Background: Allelic variation in apolipoprotein E (APOE) is by far the greatest contributor to Alzheimer's disease (AD) after age, but the mechanisms underlying how APOE impacts on the pathology of AD remain undefined. While most research is focusing on mechanisms associated with the presence of the APOE risk allele, several aspects of APOE biology remain poorly understood. In particular, the physiological relevance of APOE receptors and their impact on disease progression have been overlooked.

Basic Science and Pathogenesis.

Background: Elevated iron in brain is a source of free radicals that causes oxidative stress which has been linked to neuropathologies and cognitive impairment among older adults. The aim of this study was to investigate the association of iron levels with transverse relaxation rate, R, and white matter hyperintensities (WMH), independent of the effects of other metals and age-related neuropathologies.

Method: Cerebral hemispheres from 437 older adults participating in the Rush Memory and Aging Project study (Table 1) were imaged ex-vivo using 3T MRI scanners.

Basic Science and Pathogenesis.

Background: The glymphatic system has been suggested as an important clearance mechanism for amyloid-β (Aβ) during sleep. Animal and cellular models have suggested this clearance mechanism involves the water-channel protein, Aquaporin-4 (encoded by the AQP4 gene), located primarily in the astrocytic end-feet. We have previously reported on the interaction between genetic variants within AQP4, sleep and cross-sectional cortical amyloid-β (Aβ) burden.