Biology subjects

Saido, T. C.

Publications and source records attributed to Saido, T. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Clusterin regulates microglial inflammation and cognitive function independent of amyloid pathology in Alzheimer's disease

Clusterin (CLU) is a major genetic risk factor for late-onset Alzheimers disease (AD), yet the mechanism underlying this risk remains unclear. This study investigated the role of CLU in regulating microglial inflammation, amyloid pathology, and cognitive function in CLU-deficient and AD models. CLU synthesis and secretion in microglia were highly dynamic, with minimal expression at rest but markedly increased expression upon pro-inflammatory stimulation. CLU deficiency amplified microglial activation and inflammatory responses, whereas introducing recombinant CLU protein reduced microglial inflammation. In a human mutant APP knock-in AD mouse model, loss of CLU impaired learning and memory despite a reduced amyloid burden. snRNA-seq analysis further revealed that CLU loss disrupted the balance between excitatory and inhibitory neurons. These findings provide novel insights indicating that CLU likely functions as a negative feedback regulator of microglial activation and inflammation, thereby promoting microglial resolution and neuronal homeostasis, and consequently, cognitive outcomes independent of amyloid pathology.

neuroscience↗

bioRxiv2025

Age-Dependent, Odorant-Specific Changes in Olfactory Sensitivity in an Alzheimer's Disease Mouse Model

BackgroundOlfactory impairment often precedes cognitive decline in Alzheimers disease (AD). Recent studies suggest odor specificity in olfactory deficits during early AD stages, making olfactory tests a promising tool for early diagnosis. However, the mechanisms underlying olfactory impairment remain unclear, complicating the identification of optimal odorants for diagnostic purposes. ObjectiveIn this study, we assessed olfactory sensitivity in a knock-in mouse model of Alzheimers disease (AppNL-G-F mice) that recapitulates key features of human AD pathology. MethodsTo evaluate odor detection thresholds, we employed an olfactory assay that leverages innate behavior without requiring associative learning. Six odorants representing distinct functional groups were tested in wild-type (WT) and AppNL-G-F mice at 2 and 4 months of age. ResultsAppNL-G-F mice exhibited odorant-specific hyposmia at 4 months of age, coinciding with amyloid deposition in cortical and subcortical regions but preceding measurable cognitive deficits. Unexpectedly, at an earlier stage (2 months), these mice showed odorant-specific hyperosmia to ester odorants, which transitioned to hyposmia by 4 months, indicating dynamic, age-dependent alterations in olfactory sensitivity as AD pathology progresses. ConclusionsOur findings demonstrate that odorant-specific olfactory testing could serve as a promising diagnostic tool for early-stage AD, providing insights into the mechanisms underlying olfactory dysfunction in neurodegenerative diseases.

pathology↗

bioRxiv2025

Divergent Effects of APOE3 and APOE4 Human Astrocytes on Key Alzheimer's Disease Hallmarks in Chimeric Mice

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimers disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to A{beta} plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate A{beta} pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to A{beta} pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around A{beta} plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to A{beta} pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.

neuroscience↗

bioRxiv2025

Involvement of orexin nerves in early stage of Alzheimer's disease model mice and preventive effect of orexin receptor antagonists

BackgroundMild cognitive impairment (MCI) is a condition between healthy cognition and dementia with a high probability of progression to Alzheimers disease (AD). Elevated levels of orexin (OX) have been reported in the cerebrospinal fluid of patients with MCI and AD. ObjectiveTo investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI). MethodsThe expression of the OX receptor gene, the levels of suvorexant and lemborexant in the brain after a single oral dose, and their effects on locomotor activity were investigated in wild-type mice. In addition, the cognitive function of wild-type and App-KI mice was assessed using the Y-maze test after oral administration of suvorexant or lemborexant once a day for 60 d. After the behavioral test, amyloid-beta levels were quantified in the hippocampal CA1 region of App-KI mice. ResultsThe expression of the OX receptor gene was highest in the lateral hypothalamus and was also observed in other brain regions. Drug levels peaked at 20-40 min for suvorexant and 15 min for lemborexant and declined, still detectable 24 h later. Locomotor activity was reduced after suvorexant or lemborexant administration; however, 24 h after administration, locomotor activity did not differ from the control group. In particular, the Y-maze test showed that suvorexant and lemborexant prevented cognitive impairment in App-KI mice. Furthermore, suvorexant and lemborexant suppressed amyloid-beta accumulation in the hippocampal CA1 region of App-KI mice. ConclusionThe results suggest that suvorexant and lemborexant effectively suppress the early stages of AD.

animal behavior and cognition↗

bioRxiv2025

Misclassification in memory modification in AppNL-G-F knock-in mouse model of Alzheimers disease

Alzheimers disease (AD), the leading cause of dementia, could potentially be mitigated through early detection and interventions. However, it remains challenging to assess subtle cognitive changes in the early AD continuum. Computational modeling is a promising approach to explain a generative process underlying subtle behavioral changes with a number of putative variables. Nonetheless, internal models of the patient remain underexplored in AD. Determining the states of an internal model between measurable pathological states and behavioral phenotypes would advance explanations about the generative process in earlier disease stages beyond assessing behavior alone. In this study, we assumed the latent cause model as an internal model and estimated internal states defined by the model parameters being in conjunction with measurable behavioral phenotypes. The 6- and 12-month-old AppNL-G-F knock-in AD model mice and the age-matched control mice underwent memory modification learning, which consisted of classical fear conditioning, extinction, and reinstatement. The results showed that AppNL-G-F mice exhibited a lower extent of reinstatement of fear memory. Computational modeling revealed that the deficit in the AppNL-G-F mice would be due to their internal states being biased toward overgeneralization or overdifferentiation of their observations, and consequently the competing memories were not retained. This deficit was replicated in another type of memory modification learning in the reversal Barnes maze task. Following reversal learning, AppNL- G-F mice, given spatial cues, failed to infer coexisting memories for two goal locations during the trial. We concluded that the altered internal states of AppNL-G-F mice illustrated their misclassification in the memory modification process. This novel approach highlights the potential of investigating internal states to precisely assess cognitive changes in early AD and multidimensionally evaluate how early interventions may work.

neuroscience↗

bioRxiv2024

Age and amyloidβ-dependent initiation of neurofibrillary tau tangles: an improved mouse model of Alzheimers disease without mutations in MAPT.

The lack of models in which ageing and amyloid-{beta} (A{beta}) initiate neurofibrillary tau tangles, independent of MAPT mutations, limits mechanistic insights into Alzheimers disease. Here, we characterise NLFTaum/h, a novel mouse model that recapitulates the gradual transition from A{beta} accumulation to tau pathology by 24 months. We show that combined effects of ageing, A{beta}, and human tau expression promote tau pathology. However, either A{beta} plaques or human tau alone can initiate tau pathology, but only in even older mice. This may be exacerbated by increased neuronal vulnerability across all genotypes with age. Moreover, multi-omic analyses reveal that human tau can induce early alterations in mitochondrial and synaptic pathways, priming this latent vulnerability preceding tau pathology. Together, this suggests that ageing and other interacting triggers accelerate the onset of tau pathology. This opens possibilities for translatable testing of improved therapies for Alzheimers disease, breaking the link between A{beta} and tau pathologies.

neuroscience↗

bioRxiv2024

Early disruption of entorhinal dopamine in a knock-in model of Alzheimer's disease

The entorhinal cortex (EC) is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimers disease (AD). The EC thus has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. We found that dopamine neurons projecting their axons to the lateral EC (LEC), critical for memory formation in healthy brains, become dysfunctional and cause memory impairments in early AD brains. In amyloid precursor protein knock-in mice with associative memory impairment, LEC dopamine activity and associative memory encoding of LEC layer 2/3 neurons were disrupted in parallel from the early pathological stage. Optogenetic reactivation of LEC dopamine fibers, as well as L- DOPA treatment, rescued associative learning behavior. These results suggest that dysfunction of LEC-projecting dopamine neurons underlies memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in AD patients.

neuroscience↗

bioRxiv2024

Long term rescue of Alzheimer deficits in vivo by one-time gene-editing of App C-terminus.

Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can manipulate upstream pathophysiologic events and alter disease-course in wider patient populations. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimers disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus in mouse and human neurons, while preserving N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway; inhibiting toxic APP-beta-cleavage fragments (including Abeta) and upregulating neuroprotective APP-alpha-cleavage. AAV-editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months with no detectable abnormalities in germline-edited WT mice, and pathologic alterations in glial-transcriptomes are also normalized. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and this upstream manipulation is expected to be effective for all forms of AD.

neuroscience↗

bioRxiv2024

Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils

Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-{beta} (A{beta}) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial A{beta} uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar A{beta} phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of A{beta} fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with A{beta} uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial A{beta} uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related A{beta} accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial A{beta} clearance and highlight the therapeutic potential of GPR34 agonists in AD. Significance statementAlzheimer disease (AD) is characterized by amyloid-{beta} (A{beta}) accumulation in the brain. Microglia, the brains immune cells, play a crucial role in the metabolism of A{beta}. We discovered that activating the microglial receptor GPR34 with a selective agonist enhances the phagocytosis of A{beta} fibrils, a key pathogenic form of A{beta}. Importantly, GPR34 expression decreases with aging and AD progression, potentially contributing to impaired A{beta} clearance. Our findings highlight GPR34 as a promising therapeutic target for AD, as boosting its activity could promote A{beta} clearance and slow disease progression. This study provides valuable insights into microglial function in AD and offers a novel strategy for developing disease-modifying therapies.

neuroscience↗

bioRxiv2024

Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knock in mouse model of Alzheimer's disease.

The diseases trajectory of Alzheimers disease (AD) is associated with and worsened by hippocampal hyperexcitability. Here we show that during the asymptomatic stage in a knock in mouse model of Alzheimers disease (APPNL-G-F/NL-G-F; APPKI), hippocampal hyperactivity occurs at the synaptic compartment, propagates to the soma and is manifesting at low frequencies of stimulation. We show that this aberrant excitability is associated with a deficient adenosine tone, an inhibitory neuromodulator, driven by reduced levels of CD39/73 enzymes, responsible for the extracellular ATP-to-adenosine conversion. Both pharmacologic (adenosine kinase inhibitor) and non-pharmacologic (ketogenic diet) restorations of the adenosine tone successfully normalize hippocampal neuronal activity. Our results demonstrated that neuronal hyperexcitability during the asymptomatic stage of a KI model of Alzheimers disease originated at the synaptic compartment and is associated with adenosine deficient tone. These results extend our comprehension of the hippocampal vulnerability associated with the asymptomatic stage of Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/590882v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@cd128forg.highwire.dtl.DTLVardef@17d7701org.highwire.dtl.DTLVardef@100337org.highwire.dtl.DTLVardef@14333d0_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LISynaptic hyperexcitability spreads to the soma and manifests at low frequencies of stimulation C_LIO_LISynaptic hyperexcitability is associated with reduced adenosine tone in vitro and in vivo C_LIO_LIReduced adenosine tone is driven by reduced ATP-to-adenosine extracellular conversion C_LIO_LIRestoration of adenosine tone successfully normalizes neuronal excitability in the AD model C_LI

neuroscience↗

bioRxiv2024

Metabolic resistance of Abeta3pE-42, epitope of the anti-Alzheimer therapeutic antibody, donanemab.

The amyloid {beta} peptide (A{beta}) starting with pyroglutamate (pE) at position 3 and ending at position 42 (A{beta}3pE-42) is a dominant species that accumulates in the Alzheimers disease (AD) brain. Consistently, a therapeutic antibody raised against this species, donanemab, has been shown to be effective in recent clinical trials. While the primary A{beta} species produced physiologically is A{beta}1-40/42, an explanation for how and why this physiological A{beta} is converted to the pathological form has remained elusive. The conversion of A{beta}1-42 to A{beta}3pE-42 is likely to take place after deposition of A{beta}1-42 given that A{beta}3pE-42 plaques arise significantly later than A{beta}1-42 deposition in the brains of single App knock-in and APP-transgenic mice. Here, we present experimental evidence that accounts for the aging-associated A{beta}3pE-42 deposition: [1] A{beta}3pE-42 is metabolically more stable than other A{beta}X-42 species; [2] Deficiency of neprilysin (NEP), the major A{beta}-degrading enzyme, induces a relatively selective deposition of A{beta}3pE-42 in APP-Tg mice. [3] A{beta}3pE-42 deposition always colocalizes with cored plaques in both APP-Tg and App knock-in mouse brains; [4] A{beta}3E-42, an immediate precursor of A{beta}3pE-42, as well as A{beta}2A-42 and A{beta}4F-42 are more short-lived than A{beta}1-42 in vivo, indicating that simple N-terminal truncation that can arise enzymatically or spontaneously makes A{beta}X-42 easier to catabolize. Consistently, newly generated knock-in mice, AppNL-({Delta}DA)-F and AppNL-({Delta}DA)-Q-F, showed no detectable A{beta} pathology even after aging, indicating that the A{beta}3E-42 and A{beta}3Q-42 species are extremely labile to the in vivo catabolic system and that the E/Q cyclase activity present in mouse brain is insufficient for A{beta}3pE-42 generation. In addition, a deficiency of NEP facilitated A{beta}3pE-42 deposition. Of note, we identified a trace amount of A{beta}3pE-42 and its immediate precursor, A{beta}3E-42, in the insoluble fraction of NEP-deficient APP-Tg mouse brains. A{beta}3pE-42 is thus likely to be a probabilistic by-product of A{beta}1-42 metabolism that selectively accumulates over a long-time range of brain aging. It is likely produced in the solid state or at the solid-liquid interface. Our findings suggest that anti-A{beta} therapies will probably be most effective if given before A{beta}3pE-42 deposition takes place.

neuroscience↗

bioRxiv2023

Divergent age-dependent conformational rearrangement within Aβ-amyloid deposits in APP23, APPPS1, and AppNL-F mice

Amyloid plaques composed of fibrils of misfolded A{beta} peptides are pathological hallmarks of Alzheimers disease (AD). A{beta} fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potency and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of A{beta} fibrils is valuable to understand disease mechanisms. Here, we investigated how A{beta} fibril morphology in situ differs in A{beta} plaque of different mouse models expressing familial mutations in the A{beta}PP gene. We used a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands, A{beta}-specific antibodies, and different fluorescence microscopy techniques. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures depending on A{beta}PP-processing genotype. Co-staining of A{beta}-specific antibodies showed that individual plaques from APP23 mice, expressing Swedish mutations (NL) have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact A{beta}40 fibrils and the corona region is dominated by diffusely packed A{beta}40 fibrils. On the other hand, the APP knock-in mouse AppNL-F, expressing Iberian mutation (F) along with Swedish mutation has tiny, cored plaques consisting mainly of compact A{beta}42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age dependent polymorph maturation of plaque cores observed for APP23 and APPPS1 mice >12 months, was minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules. SignificanceAlzheimers disease (AD) is associated with the formation of deposits in the brain known as A{beta}-amyloid plaques. AD can emerge as a sporadic disease or due to familial mutations in genes encoding for A{beta} precursor and processing proteins. The A{beta}-amyloid found in plaques displays different structures in sporadic AD and in various types of familial AD. We hypothesize that understanding plaque morphology and development is crucial for understanding the initiation and progression of AD. We here compared amyloid structures in three of the most used mouse models of human A{beta}-plaque formation. Our findings suggest significant differences in plaque morphologies and structural maturation processes during aging. Our results emphasize that strain-like differences of A{beta}-amyloids develop as a function of A{beta} precursor protein-processing genetics and age.

neuroscience↗

bioRxiv2022

Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's Disease

Microglial endolysosomal (dys)function is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimers Disease (AD) models and in human AD brain and that the onset of this state is emphasized in females. Cst7 (encoding protein Cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the sex-specific function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7-/- mice with the AppNL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD. Surprisingly, we found that Cst7 plays a sexually dimorphic role regulating microglia in this model. In females, Cst7-deficient microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (A{beta}) burden in vivo and were more phagocytic in vitro. However, in males, Cst7-deficient microglia were less inflammatory and had a reduction in lysosomal burden but had no change in A{beta} burden. This study has important implications for AD research, confirming the functional role of a gene which is commonly upregulated in disease models, but also raising crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.

neuroscience↗

bioRxiv2022

Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-{beta} (A{beta})], causes dominantly inherited Alzheimers disease. Here we report the high-resolution cryo-EM structures of A{beta} filaments from the frontal cortex of a previously described case (A{beta}PParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II A{beta}42. When compared to the structures of wild-type A{beta}42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant A{beta} molecules and promote filament formation. A minority of A{beta}42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of A{beta} filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1-G37 (murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The murine Arctic fold differs from the human Arctic folds, but shares some substructure.

neuroscience↗

bioRxiv2022

A novel fully-automated system for lifelong continuous phenotyping of mouse cognition and behaviour

Comprehensive ethologically-relevant behavioural phenotyping in rodent experiments is essential for deciphering the neural basis of animal cognition. Automated home-cage monitoring systems present a valuable tool to fulfil this need. However, they often involve complex animal training routines, water or food deprivation, and probe a limited range of behaviours. Here, we present a new fully automated AI-driven home-cage system for cognitive and behavioural phenotyping in mice. The system incorporates spontaneous alternation T-maze, novel-object recognition and object-in-place recognition tests combined with monitoring of an animals position, water consumption, quiescence and locomotion patterns, all carried out continuously and simultaneously in an unsupervised fashion over long periods of time. Mice learnt the tasks rapidly without any need for water or food restrictions. We applied ethomics approach to show that combined statistical properties of multiple behaviours can be used to discriminate between mice with hippocampal, medial entorhinal and sham lesions and accurately predict genotype of Alzheimers disease mouse models on an individual animal level, surpassing the performance of several gold standard cognitive tests. This technology could enable large-scale behavioural screening for genes and neural circuits underlying spatial memory and other cognitive processes.

neuroscience↗

bioRxiv2022

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. We show that TSPO is mechanistically linked to classical pro-inflammatory myeloid cell function in rodents but not humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than activation state.

neuroscience↗

bioRxiv2022

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome frequently develop early onset Alzheimers disease, a neurodegenerative condition caused by the build-up of aggregated amyloid-{beta} and tau proteins in the brain. Amyloid-{beta} is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimers disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-{beta} accumulation (AppNL-F) to determine how chromosome 21 genes other than APP modulate APP/amyloid-{beta} in the brain when in three copies. We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-{beta} accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-{beta} accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-{beta} in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS compared to those who have familial AD caused by triplication of APP.

neuroscience↗

bioRxiv2021

An isogenic panel of single App knock-in mouse models of Alzheimer's disease confers differential profiles of β-secretase inhibition and endosomal abnormalities

We previously developed single App knock-in mouse models of Alzheimers disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL- G-F and AppNL-F mice). These models showed the development of amyloid {beta} peptide (A{beta}) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of {beta}-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by {beta}-secretase (CTF-{beta}) affect endosomal properties as previously reported as well as other pathological events? A{beta} pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a {beta}-secretase inhibitor, verubecestat, inhibited A{beta} production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of {beta}-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-{beta} generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-{beta}, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.

neuroscience↗