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The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide....

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Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC...

Haemoglobin is a ferrous iron (Fe^(2+))-containing intracellular protein that is crucial for multiple homeostatic functions, including transport of oxygen and carbon dioxide, acid-base buffering and cellular signalling through nitric oxide oxidation and nitrite reduction. When erythrocyte membranes are disrupted, a process known as haemolysis that is caused by either disease or an exogenous stressor, haemoglobin is liberated into the plasma. This plasma free haemoglobin is highly pathogenic,...

CONCLUSION: The current evidence does not establish a definitive APOE ε4-specific preventive effect of PA. Future studies may be most informative if they target earlier-stage, low-active, or metabolically at-risk APOE ε4 carriers using objective PA measures and proximal vascular, metabolic, imaging, or blood-based biomarker outcomes.

A new wearable patch may help people reach REM sleep faster and remain there longer without medication or surgery. In a study of 28 participants, the device shortened the time to REM by 43 minutes and extended it by about 16 minutes. Researchers also observed signs of improved stress regulation and changes in brain circuits tied to emotion.

Beginning around age 50, the brain’s memory center appears to lose many of its longtime immune cells and replace them with more inflammatory ones. This surprising shift may help explain how normal aging sets the stage for Alzheimer’s disease and dementia.

Study of mitochondria suggests new treatment strategy for Alzheimer’s and other diseases

A long-term brain study found that common risks such as smoking, high blood pressure, heart disease, and high blood lipids were strongly linked to damage associated with vascular dementia. The findings suggest that healthier lifestyle choices could help delay dementia by reducing several harmful brain changes at once.

Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD^(+)/NADH ratio, and is activated...

Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress....

The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson's disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show...

Classical evolutionary theories of aging, including antagonistic pleiotropy (AP) and the disposable soma theory (DST), explain why aging exists but are often applied without considering how sex-specific reproductive strategies shape the forces of natural selection on survival. They do not explain why females consistently outlive males across taxa, despite their greater reproductive investment, or why in some contexts, such as eusocial queens, extraordinary fecundity is coupled with exceptional...

Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD^(+)/NADH ratio, and is activated...

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major challenges in critical care medicine, characterized by alveolar-capillary barrier disruption, excessive inflammation, and impaired gas exchange. With the growing aging population, aging has emerged as an important determinant of ALI/ARDS susceptibility, progression, and prognosis. Aging promotes pulmonary vulnerability through multiple interconnected mechanisms, including immune dysregulation,...

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Regular physical exercise is essential for promoting healthy aging and longevity. In older adults with varying physical and cognitive decline, optimising exercise interventions is crucial to maximise benefits. A promising approach to achieve this goal is by adjusting task demands to individual abilities in turn preventing over- or underloading their abilities. In the field of motor learning, it is currently unclear whether such an optimised training improves not only performance on the trained...