Citations

Abstract INTRODUCTION Loss‐of‐function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. METHODS Using neuron‐specific Abca7 KO mice (n Abca7 −/− ) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD‐related phenotypes through comprehensive approaches including transcriptomics and lipidomics. RESULTS Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; n Abca7 −/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; n Abca7 −/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains. DISCUSSION Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology. Highlights Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aβ42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aβ42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aβ42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractBackgroundThe immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).MethodAs genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.ResultWe found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aß42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aß42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aß42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.ConclusionTogether, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.

AbstractINTRODUCTIONThe apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid‐beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex‐dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.METHODSIn 2023, the Alzheimer's Association convened multidisciplinary researchers at the “AAIC Advancements: APOE” conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE‐targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function.RESULTSThis manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field.DISCUSSIONUnderstanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine.Highlights APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer’s disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell–specific Lrp1 -KO mice ( smLrp1 –/– ) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1 –/– mice but not in the APOE3 smLrp1 –/– mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1 –/– mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1 –/– mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype–dependent manner.

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.

Abstract Background: The p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site and was shown to enhance shedding and impair phagocytosis in vitro by ectopic expression of TREM2-H157Y in HEK293 cells. However, the physiological and AD-related outcomes of TREM2 H157Y mutation in vivo remain unknown.Methods: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR-Cas9 technology and investigated how Trem2 H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathology by conducting biochemical assays, immunofluorescent staining, hippocampal electrophysiology, and in vivo micro-dialysis in awake, free-moving animals.Results: Consistent with previous in vitro findings, TREM2-H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2-H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis. Conclusion: Taken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2-H157Y might increase AD risk through an amyloid-independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.