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Abstract Alzheimer’s disease (AD), characterized by the deposition of amyloid-β (Aβ) in senile plaques and neurofibrillary tangles of phosphorylated tau (pTau), is increasingly recognized as a complex disease with multiple pathologies. AD sometimes pathologically overlaps with age-related tauopathies such as four repeat (4R)-tau predominant argyrophilic grain disease (AGD). While AGD is often detected with AD pathology, the contribution of APOE4 to AGD risk is not clear despite its robust effects on AD pathogenesis. Specifically, how APOE genotype influences Aβ and tau pathology in co-occurring AGD and AD has not been fully understood. Using postmortem brain samples (N = 353) from a neuropathologically defined cohort comprising of cases with AD and/or AGD pathology built to best represent different APOE genotypes, we measured the amounts of major AD-related molecules, including Aβ40, Aβ42, apolipoprotein E (apoE), total tau (tTau), and pTau181, in the temporal cortex. The presence of tau lesions characteristic of AD (AD-tau) was correlated with cognitive decline based on Mini-Mental State Examination (MMSE) scores, while the presence of AGD tau lesions (AGD-tau) was not. Interestingly, while APOE4 increased the risk of AD-tau pathology, it did not increase the risk of AGD-tau pathology. Although APOE4 was significantly associated with higher levels of insoluble Aβ40, Aβ42, apoE, and pTau181, the APOE4 effect was no longer detected in the presence of AGD-tau. We also found that co-occurrence of AGD with AD was associated with lower insoluble Aβ42 and pTau181 levels. Overall, our findings suggest that different patterns of Aβ, tau, and apoE accumulation mediate the development of AD-tau and AGD-tau pathology, which is affected by APOE genotype.

Abstract Background Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear. Methods To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination. Results We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice. Conclusions Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.

Abstract Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.

Lynx1 is a glycosylphosphatidylinositol (GPI)-linked protein shown to affect synaptic plasticity through modulation of nicotinic acetylcholine receptor (nAChR) subtypes in the brain. Because of this function and structural similarity to α-bungarotoxin, which binds muscle-specific nAChRs with high affinity, Lynx1 is a promising candidate for modulating nAChRs in skeletal muscles. However, little is known about the expression and roles of Lynx1 in skeletal muscles and neuromuscular junctions (NMJs). Here, we show that Lynx1 is expressed in skeletal muscles, increases during development, and concentrates at NMJs. We also demonstrate that Lynx1 interacts with muscle-specific nAChR subunits. Additionally, we present data indicating that Lynx1 deletion alters the response of skeletal muscles to cholinergic transmission and their contractile properties. Based on these findings, we asked if Lynx1 deletion affects developing and adult NMJs. Loss of Lynx1 had no effect on NMJs at postnatal day 9 (P9) and moderately increased their size at P21. Thus, Lynx1 plays a minor role in the structural development of NMJs. In 7- and 12-month-old mice lacking Lynx1, there is a marked increase in the incidence of NMJs with age- and disease-associated morphological alterations. The loss of Lynx1 also reduced the size of adult muscle fibers. Despite these effects, Lynx1 deletion did not alter the rate of NMJ reinnervation and stability following motor axon injury. These findings suggest that Lynx1 is not required during fast remodeling of the NMJ, as is the case during reformation following crushing of motor axons and development. Instead, these data indicate that the primary role of Lynx1 may be to maintain the structure and function of adult and aging NMJs.