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The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer’s disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.

Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.

INTRODUCTION Previous simulations of Hebbian associative memory models inspired the malignant synaptic growth hypothesis of Alzheimer's disease (AD), which suggests that cognitive impairments arise due to runaway synaptic modification resulting from poor separation between encoding and retrieval. METHODS We computationally model presynaptic inhibition by the recently identified interaction of soluble amyloid precursor protein alpha (sAPPα) with γ‐aminobutyric acid type B receptor (GABABR) as one potential biological mechanism that can enhance separation between encoding and retrieval. RESULTS Simulations predict that the dual effect of sAPPα on long‐term potentiation and presynaptic inhibition of glutamatergic synapses maintains effective associative memory function and prevents runaway synaptic modification. Moreover, computational modeling predicts that sAPPα, which interacts with the 1a isoform of GABABR, is more effective than the GABABR agonist baclofen at stabilizing associative memory. DISCUSSION Molecular mechanisms that enhance presynaptic inhibition, such as sAPPα‐GABABR1a signaling, are potential therapeutic targets for preventing cognitive impairments in AD. Highlights Computational modeling of Hebbian associative memory provides a framework for understanding the functional basis of Alzheimer's disease. Soluble amyloid precursor protein (sAPPα) presynaptic activation of γ‐aminobutyric acid B (GABAB) receptors prevents runaway synaptic modification in associative memory models. sAPPα is more effective than baclofen at stabilizing associative memory.

A physiological function for sAPP?Although the pathological role of the amyloid-β precursor protein (APP) in Alzheimer's disease is well studied, the physiological role of this protein has remained elusive. Rice et al. found that the secreted ectodomain of APP (sAPP) binds to GABABR1a, the metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (see the Perspective by Korte). Binding suppressed synaptic vesicle release and modulated synaptic transmission and plasticity in mice. A short, 17–amino acid peptide in APP bound to GABABR1a's sushi 1 domain, conferring structure to this unstructured domain. Therapeutics targeting this interaction could potentially benefit a range of neurological disorders in which GABA signaling is implicated.Science, this issue p. eaao4827; see also p. 123INTRODUCTIONMore than 30 years have passed since the amyloid-β precursor protein (APP) was identified. Although the role of APP in Alzheimer’s disease has been studied widely, its normal physiological function in the brain has remained elusive. APP undergoes ectodomain shedding by α-, β-, or η-secretase to release secreted APP (sAPPα, sAPPβ, or sAPPη, respectively). sAPPα affects synaptic transmission and plasticity and is sufficient to rescue synaptic defects in App knockout mice. This has led to speculation of a yet unidentified cell-surface receptor for sAPPα.RATIONALETo elucidate the physiological function of APP, we sought to identify the cell-surface receptor mediating its effects on synaptic function. To identify candidate synaptic interactors for sAPPα, we performed affinity-purification experiments using recombinant sAPPα to pull down interacting proteins from synaptosome extracts, followed by mass spectrometric analysis of bound proteins. We identified the γ-aminobutyric acid type B receptor (GABABR), the metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid (GABA), as the leading candidate for a synaptic, cell-surface receptor for sAPPα. We then performed a combination of cell-surface binding assays and in vitro biophysical techniques to determine the interacting domains and structural consequences of binding. We investigated whether sAPPα can modulate GABABR function by assessing miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) and synaptic vesicle recycling in mouse hippocampal neuron cultures, short-term plasticity in acute hippocampal slices from mice, and in vivo neuronal activity in the hippocampus of anesthetized mice.RESULTSRecombinant sAPPα selectively bound to GABABR subunit 1a (GABABR1a)–expressing cells. Binding was mediated by the flexible, partially structured extension domain in the linker region of sAPP and the natively unstructured sushi 1 domain specific to GABABR1a. sAPPβ and sAPPη, which both contain the extension domain, also bound to GABABR1a-expressing cells. Conversely, APP family members APP-like proteins 1 and 2, which lack a conserved extension domain, failed to bind GABABR1a-expressing cells. Acute application of sAPPα reduced the frequency of mEPSCs and mIPSCs and decreased synaptic vesicle recycling in cultured mouse hippocampal neurons. In addition, sAPPα enhanced short-term facilitation in acute hippocampal slices from mice. Together, these findings demonstrate that sAPP reduces the release probability of synaptic vesicles. These effects were dependent on the presence of the extension domain in sAPP and were occluded by a GABABR antagonist. A short APP peptide corresponding to the GABABR1a binding region within APP stabilized the natively unstructured sushi 1 domain of GABABR1a, allowing determination of its solution structure using nuclear magnetic resonance spectroscopy and the generation of a structural model of the APP–sushi 1 complex. Application of a 17–amino acid APP peptide mimicked the effects of sAPPα on GABABR1a-dependent inhibition of synaptic vesicle release and reversibly suppressed spontaneous neuronal activity in vivo.CONCLUSIONWe identified GABABR1a as a synaptic receptor for sAPP and revealed a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission and plasticity. Our findings provide a potential target for the development of GABABR1a isoform–specific therapeutics, which is relevant to a number of neurological disorders in which GABABR signaling is implicated.Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for secreted APP (sAPP). Here we show that the sAPP extension domain directly bound the sushi 1 domain specific to the γ-aminobutyric acid type B receptor subunit 1a (GABABR1a). sAPP-GABABR1a binding suppressed synaptic transmission and enhanced short-term facilitation in mouse hippocampal synapses via inhibition of synaptic vesicle release. A 17–amino acid peptide corresponding to the GABABR1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABABR1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABABR1a function to modulate synaptic transmission.

Background Mitochondrial dysfunction is a key feature of Alzheimer's disease (AD). Amyloid Precursor Protein (APP), the precursor to Aβ peptides that form amyloid plaques in AD, has been shown to localize to the mitochondria under certain conditions. However, the precise role of APP in mitochondria is not fully understood, and exploring its protein‐protein interactions could provide crucial insights. Recent work by Rice et al. identified PGAM5, a mitochondrial phosphatase, as a candidate interactor of APP. PGAM5 is involved in regulating important mitochondrial processes such as fission, fusion, and mitophagy through interactions with various substrates. We sought to identify the role of APP in mitochondrial functions in health and AD through its interaction with PGAM5. Method To characterize the binding between APP and PGAM5, we performed in vitro pull‐down assays and isothermal calorimetry (ITC). Proximity ligation assays in mouse brain tissue and primary astrocytes were employed to examine the endogenous interaction of these proteins. Subcellular fractionations were performed to study the processing and localization of APP and PGAM5 in wildtype and APP NL‐G‐F mice brains. Result Pull‐down assays revealed that the linker region of APP binds to either the multimerization motif or the Keap‐1 binding domain of PGAM5. ITC demonstrated an interaction between APP and PGAM5. Endogenous interactions between APP and PGAM5 were detected in the brains of healthy mice and primary astrocytes, with potential location of this interaction being the mitochondria‐associated membranes (MAMs). Brain fractionation data demonstrated that both PGAM5 and full‐length APP (APP‐FL) were present in MAMs, while APP carboxy‐terminal fragments (APP‐CTF) localized to mitochondria along with PGAM5. Additionally, PGAM5 cleavage was found to be reduced in the brains of older AD mice. Conclusion Our findings suggest that APP and PGAM5 interact under physiological conditions. In AD, the decreased cleavage of PGAM5 may impair mitophagy, contributing to the mitochondrial dysfunction seen in AD pathogenesis. Precise understanding of the interaction of APP with other proteins, like PGAM5 is critical to ensure the long‐term safety of potential treatments like APP knockdown in AD patients.

Mitochondrial dysfunction is a key feature of Alzheimer's disease (AD). Amyloid Precursor Protein (APP), the precursor to Aβ peptides that form amyloid plaques in AD, has been shown to localize to the mitochondria under certain conditions. However, the precise role of APP in mitochondria is not fully understood, and exploring its protein-protein interactions could provide crucial insights. Recent work by Rice et al. identified PGAM5, a mitochondrial phosphatase, as a candidate interactor of APP. PGAM5 is involved in regulating important mitochondrial processes such as fission, fusion, and mitophagy through interactions with various substrates. We sought to identify the role of APP in mitochondrial functions in health and AD through its interaction with PGAM5. To characterize the binding between APP and PGAM5, we performed in vitro pull-down assays and isothermal calorimetry (ITC). Proximity ligation assays in mouse brain tissue and primary astrocytes were employed to examine the endogenous interaction of these proteins. Subcellular fractionations were performed to study the processing and localization of APP and PGAM5 in wildtype and APP NL-G-F mice brains. Pull-down assays revealed that the linker region of APP binds to either the multimerization motif or the Keap-1 binding domain of PGAM5. ITC demonstrated an interaction between APP and PGAM5. Endogenous interactions between APP and PGAM5 were detected in the brains of healthy mice and primary astrocytes, with potential location of this interaction being the mitochondria-associated membranes (MAMs). Brain fractionation data demonstrated that both PGAM5 and full-length APP (APP-FL) were present in MAMs, while APP carboxy-terminal fragments (APP-CTF) localized to mitochondria along with PGAM5. Additionally, PGAM5 cleavage was found to be reduced in the brains of older AD mice. Our findings suggest that APP and PGAM5 interact under physiological conditions. In AD, the decreased cleavage of PGAM5 may impair mitophagy, contributing to the mitochondrial dysfunction seen in AD pathogenesis. Precise understanding of the interaction of APP with other proteins, like PGAM5 is critical to ensure the long-term safety of potential treatments like APP knockdown in AD patients.

Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome trafficking/turnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.

Major histocompatibility complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses, but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). Here, we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating ribosome affinity purification-qPCR analysis of 3–6- and 18–22-month-old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m , H2-D1 , H2-K1 , H2-M3 , H2-Q6 , and Tap1 but not in astrocytes and neurons. Across a timecourse (12–23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I-binding leukocyte immunoglobulin-like (Lilrs) and paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell -autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A , suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.

Abstract The greatest risk factor for cognitive decline is aging. The biological mechanisms for this decline remain enigmatic due, in part, to the confounding of normal aging mechanisms and those that contribute to cognitive impairment. Importantly, many individuals exhibit impaired cognition in age, while some retain functionality despite their age. Here, we establish a behavioral testing paradigm to characterize age-related cognitive heterogeneity in inbred aged C57BL/6 mice and reliably separate animals into cognitively “intact” (resilient) and “impaired” subgroups using a high-resolution home-cage testing paradigm for spatial discrimination. RNA sequencing and subsequent pathway analyses of cognitively stratified mice revealed molecular signatures unique to cognitively impaired animals, including transcriptional down-regulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and sirtuin (Sirt1 and Sirt3) expression in the hippocampus. Mitochondrial function assessed using high-resolution respirometry indicated a reduced OXPHOS coupling efficiency in cognitively impaired animals with subsequent hippocampal analyses revealing an increase in the oxidative damage marker (3-nitrotyrosine) and an up-regulation of antioxidant enzymes (Sod2, Sod1, Prdx6, etc.). Aged–impaired animals also showed increased levels of IL-6 and TNF-α gene expression in the hippocampus and increased serum levels of proinflammatory cytokines, including IL-6. These results provide critical insight into the diversity of brain aging in inbred animals and reveal the unique mechanisms that separate cognitive resilience from cognitive impairment. Our data indicate the importance of cognitive stratification of aging animals to delineate the mechanisms underlying cognitive impairment and test the efficacy of therapeutic interventions.

Although the pathological role of the amyloid-β precursor protein (APP) in Alzheimer's disease is well studied, the physiological role of this protein has remained elusive. Rice et al. found that the secreted ectodomain of APP (sAPP) binds to GABA B R1a, the metabotropic receptor for the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (see the Perspective by Korte). Binding suppressed synaptic vesicle release and modulated synaptic transmission and plasticity in mice. A short, 17–amino acid peptide in APP bound to GABA B R1a's sushi 1 domain, conferring structure to this unstructured domain. Therapeutics targeting this interaction could potentially benefit a range of neurological disorders in which GABA signaling is implicated. Science , this issue p. eaao4827 ; see also p. 123 Amyloid-β precursor protein suppresses vesicle release from presynaptic boutons by binding to the GABA B 1a receptor. Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological function remains unresolved. Accumulating evidence suggests that APP has a synaptic function mediated by an unidentified receptor for secreted APP (sAPP). Here we show that the sAPP extension domain directly bound the sushi 1 domain specific to the γ-aminobutyric acid type B receptor subunit 1a (GABA B R1a). sAPP-GABA B R1a binding suppressed synaptic transmission and enhanced short-term facilitation in mouse hippocampal synapses via inhibition of synaptic vesicle release. A 17–amino acid peptide corresponding to the GABA B R1a binding region within APP suppressed in vivo spontaneous neuronal activity in the hippocampus of anesthetized Thy1-GCaMP6s mice. Our findings identify GABA B R1a as a synaptic receptor for sAPP and reveal a physiological role for sAPP in regulating GABA B R1a function to modulate synaptic transmission.