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Neuroinflammation contributes to Alzheimer's disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.

In psychology and neuroscience, scientific questions are often framed in terms of mental activity (e.g., cognition, emotion, and perception); however, the brain is an organ with a particular function that only it can fulfill. Converging evidence suggests that this function is allostasis: the predictive regulation of competing demands from internal bodily systems. We review evidence for a distributed allostatic system that organizes whole-brain signaling, scaffolds psychological phenomena, and...

This systematic review investigates the timeline of Alzheimer's disease (AD)-like changes in the intracerebroventricular streptozotocin (ICV-STZ) rat model, a key tool for studying sporadic, non-genetic forms of AD. Following PRISMA guidelines, we analyzed 402 studies to characterize the progression of key pathological features, including cognitive deficits, insulin resistance, neurodegeneration, neuroinflammation, oxidative stress, tau pathology, amyloid aggregation, blood-brain barrier (BBB)...

Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a...

Aging cells functionally decline and accumulate damage through poorly understood mechanisms. In this issue, Antentor et al. (https://doi.org/10.1083/jcb.202412064) find that increased vacuolar pH in older yeast cells slows clathrin-mediated endocytosis. These findings have broad implications in aging-related plasma membrane protein quality control.

Aging imposes a significant socioeconomic and healthcare burden worldwide, while effective therapy is still lacking. Impaired brain drainage and excessive accumulation of metabolites and toxins such as advanced glycation end products (AGEs) are characteristics of aging that contribute to the development of neurological disorders. Recent discoveries have highlighted the role of meningeal lymphatic vessels (MLVs) in the clearance of toxic metabolites, cells, tumors, and viruses from the brain,...

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in the elderly, characterized by the progressive destruction of cartilage, synovial inflammation, and subchondral bone remodeling. While mechanical stress, metabolic derangements, and systemic inflammation are recognized contributors, accumulating evidence underscores the pivotal role of impaired macroautophagy/autophagy in disease pathogenesis. Autophagy declines with age, depriving chondrocytes and...