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Lecanemab, a leading therapy for Alzheimer’s disease, induces an Fc-mediated transcriptional program in human microglia, linked to osteopontin and enhanced plaque phagocytosis, suggesting alternative strategies to promote plaque clearance.

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.

Human microglia transplanted in the mouse brain mount a multipronged response to amyloid-β pathology, displaying unique transcriptional states. Alzheimer’s disease risk genes are differentially regulated across cell states and profoundly alter microglial function.

The three secretases that process amyloid precursor protein are central to the generation of amyloid-β, and the accumulation of this peptide in extracellular plaques is one of the hallmarks of Alzheimer disease. In this Review, De Strooper et al. discuss the evidence that suggests that these enzymes are potential therapeutic targets for Alzheimer disease drug treatments.

A study now finds early memory impairment in a mouse model of amyloid β43 (Aβ43)-overproducing familial Alzheimer's disease and suggests that this overlooked amyloidogenic Aβ species contributes to pathology.

Non-coding RNAs (ncRNAs) have been implicated in the pathophysiology of various neurodegenerative diseases. In this Review, Salta and De Strooper discuss the mechanisms by which ncRNAs may be linked to neurodegeneration and touch on the use of ncRNA-based biomarkers and therapies for these conditions.

APOE is the strongest risk gene for late onset Alzheimer’s disease and its expression is upregulated in microglia in response to amyloid beta. Here, the authors show that the APOE isoforms show different transcriptomic and epigenomic responses to amyloid, by studying human microglia transplanted into the brain of an Alzheimer’s disease mouse model.

Increased neuronal activity and reduced sleep quality emerge in the early stages of Alzheimer’s disease (AD). Calafate et al. show that the sleep–active hypothalamic MCH system is involved in neuronal homeostasis but fails in the early stages of AD.

Thathiah and De Strooper discuss the complex interactions between G protein-coupled receptors (GPCRs) and the amyloid-β cascade in Alzheimer's disease, highlighting new targets for drug discovery efforts and the need for a multi-target approach to therapy.

Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development. See Letter p.512

A rare gene variant has been found that decreases the peptide deposition seen in the brains of people with Alzheimer's disease. The mutation may also slow the normal cognitive decline that occurs with age. See Letter p.96

The role of microglia in Alzheimer’s disease is debated. This paper shows that homeostatic microglia seed amyloid plaques in early disease stages and activated microglia compact plaques at later stages, clarifying previous contradictory findings.

The signaling receptor Notch is required for the generation of marginal zone B cells. Hammad and colleagues show that Notch signaling activates the kinase Taok3 and surface expression of the metalloproteinase ADAM10, which commits transitional B cells to the marginal zone B cell fate.

The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.

Many drugs that target amyloid-β in Alzheimer disease have failed in clinical trials. Karran and De Strooper analyse clinical trial data for these drugs in the light of drug properties that could affect their clinical performance. They propose that amyloid plaque would need to be reduced to a low level to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe such a benefit.

Deposition of amyloid β-peptide in cerebral vessel walls, termed cerebral amyloid angiopathy (CAA), enhances the cognitive deficits associated with Alzheimer's disease. The molecular details by which circulatory defects with hypoxia alter peptide clearance, contributing to brain deposition and AD, are beginning to be elucidated.

The amyloid cascade hypothesis — which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease (AD) pathology — has strongly influenced recent AD drug discovery efforts. However, so far all agents targeting amyloid-β have failed in Phase III trials. Here, Karran and colleagues re-evaluate the amyloid cascade hypothesis and explore the future potential of amyloid-β-targeting therapeutics.

Mancuso and De Strooper and colleagues describe MIGRATE (microglia in vitro generation refined for advanced transplantation experiments, a combined in vitro differentiation and in vivo xenotransplantation protocol for studying human microglia transplanted into mouse brain.

While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.

Liston and colleagues design a gene-delivery system to specifically target astrocytes in the central nervous system to express IL-2 and thereby expand/maintain T_reg cells to suppress neuroinflammation.

For decades, a short amyloid peptide called Aβ has been thought to underlie the neurodegeneration characteristic of Alzheimer's disease. This peptide is produced from a longer precursor protein by two protein-cleaving enzymes, known as β-secretase and γ-secretase. Presenilin, a suspect of old, is now revealed as the γ-secretase.

Mislocalisation of tau occurs in several neurodegenerative diseases and is thought to contribute to synaptic function. The authors show that presynaptically, tau binds to synaptic vesicles via the N-terminus which contributes to synaptic dysfunction.

There is no known cure for Alzheimer's disease. But new hope (for mice at least) comes from an in-depth investigation of a class of drugs used to treat inflammatory diseases.

MicroRNA-29 is known to reduce collagen production in fibroblasts thereby inhibiting fibrosis in various organs. Here, Sassi et al. show that miR-29 can also enhance fibrotic signalling and pathological hypertrophy of the heart through its action in cardiomyocytes.

Lithium, already used to treat psychiatric disorders, has been found to reduce amyloid-peptide production in a mouse model of Alzheimer's disease. The implication is that lithium's target molecule helps to generate the peptides.

Alzheimer's disease is a progressive dementia in which massive protein deposits accumulate as either amyloid plaques or neurofibrillary tangles. The plaques are composed of a peptide called Aβ, which is liberated from its precursor, the amyloid precursor protein, by cleavage at two sites. The enzyme that cleaves at one of these sites, the β site, has now been identified, and it is likely to be a good target for drugs.

Human stem cell-derived microglia integrate into mouse brain, displaying transcriptome signatures of microglia directly isolated from human brain and providing a chimeric model to study human-specific aspects of Alzheimer’s disease and other brain diseases.

Interferon-α is a critical mediator of pathogen-induced thymic involution. Liston and colleagues show that the microRNA miR-29a reduces sensitivity of thymic epithelium to infection signals and protects against thymus involution.

The γ-secretase complex is responsible for the generation of amyloid β-peptide, the main component of Alzheimer's disease associated plaques. A proteomic analysis yielded secretory pathway components and membrane-associated tetraspannin microdomains as interactors and regulators of the γ-secretase complex.

Missense mutations in the genes coding for presenilin 1 and presenilin 2 cause familial Alzheimer's disease — a progressive neurodegenerative disorder of the central nervous system. Loss-of-function mutations of these genes in Drosophila, Caenorhabditis elegans and mice cause severe lethal phenotypes, which implicates the presenilins genetically in the Notch signalling pathway. The hypothesis that presenilins are aspartyl proteases that cleave the amyloid precursor protein and Notch can explain the phenotypes. Direct evidence for this hypothesis is, however, difficult to obtain. Moreover, presenilin 1 is a multifunctional protein, as exemplified by its role in the Wnt/β-catenin signalling pathway.

A known oncogene, MITF, resides in a region of chromosome 3 that is amplified in melanomas and associated with poor prognosis; now, a long non-coding RNA gene, SAMMSON, is shown to also lie in this region, to also act as a melanoma-specific survival oncogene, and to be a promising therapeutic target for anti-melanoma therapy.

Good–bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.

This review article discusses the basis of β-amyloid's contribution to Alzheimer's disease pathology and critically examines the toxic Aβ oligomer hypothesis.

To date, all phase III trials of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) inhibitors for Alzheimer disease were either discontinued or produced negative results. Here the authors present their opinion that BACE inhibitors still hold promise as a preventative therapy for Alzheimer disease and outline a series of experiments to inform future trials.