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Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APP NL-F/NL-F knock-in (KI) mice bearing humanized ApoE3 or ApoE4 (APP;E3F and APP;E4F). As travel to a specialized facility was required for irradiation, both traveled sham-irradiated C57BL/6J WT and KI mice and non-traveled (NT) KI mice acted as controls for potential effects of travel. Mice underwent four behavioral tests at 20 months of age and were euthanized for pathological and biochemical analyses 1 month later. Fecal samples were collected pre- and post-irradiation at four different time points. GCRsim seemed to impair memory in male APP;E3F mice compared to their sham counterparts. Travel tended to improve cognition in male APP;E3F mice and lowered total Aβ in female and male APP;E3F mice compared to their non-traveled counterparts. Sham-irradiated male APP;E4F mice accumulated more fibrillar amyloid than their APP;E3F counterparts. Radiation exposure had only modest effects on behavior and brain changes, but travel-, sex-, and genotype-specific effects were seen. Irradiated mice had immediate and long-term differences in their gut bacterial composition that correlated to Alzheimer's disease phenotypes.

Understanding the hazards of space radiation is imperative as astronauts begin voyaging on missions with increasing distances from Earth's protective shield. Previous studies investigating the acute or long-term effects of specific ions comprising space radiation have revealed threats to organs generally considered radioresistant, like the brain, and have shown males to be more vulnerable than their female counterparts. However, astronauts will be exposed to a combination of ions that may result in additive effects differing from those of any one particle species. To better understand this nuance, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like mice with 0, 0.5, or 0.75 Gy galactic cosmic ray simulation (GCRsim) or 0, 0.75, or 2 Gy gamma radiation (wild-type only). At 11 months, mice underwent brain and heart MRIs or behavioral tests, after which they were euthanized to assess amyloid-beta pathology, heart and kidney gene expression and fibrosis, and plasma cytokines. Although there were no changes in amyloid-beta pathology, we observed many differences in brain MRIs and behavior, including opposite effects of GCRsim on motor coordination in male and female transgenic mice. Additionally, several genes demonstrated persistent changes in the heart and kidney. Overall, we found sex- and genotype-specific, long-term effects of GCRsim and gamma radiation on the brain, heart, and kidney.

Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers ( APOE4 ) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene ( APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy.

As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5-6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.

Space radiation presents a substantial threat to travel beyond Earth. Relatively low doses of high-energy particle radiation cause physiological and behavioral impairments in rodents and may pose risks to human spaceflight. There is evidence that 56 Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer's disease pathology in genetically vulnerable models. Yet, research on the long-term, sex- and genotype-specific effects of 56 Fe irradiation is lacking. Here, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of 56 Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. 56 Fe irradiation worsened amyloid-beta (Aβ) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. Although sham-irradiated female APP/PS1 mice had more cerebral Aβ and gliosis than sham-irradiated male transgenics, female mice of both genotypes were relatively spared from radiation effects 8 months later. These results provide evidence for sex-specific, long-term CNS effects of space radiation.

Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer's disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16-41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45-65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect.

Passive immunotherapy has emerged as a very promising approach for the treatment of Alzheimer’s disease and other neurodegenerative disorders, which are characterized by the misfolding and deposition of amyloid peptides. On the basis of the amyloid hypothesis, the majority of antibodies in clinical development are directed against amyloid β (Aβ), the primary amyloid component in extracellular plaques. This review focuses on the current status of Aβ antibodies in clinical development, including their characteristics and challenges that came up in clinical trials with these new biological entities (NBEs). Emphasis is placed on the current view of common side effects observed with passive immunotherapy, so-called amyloid-related imaging abnormalities (ARIAs), and potential ways to overcome this issue. Among these new ideas, a special focus is placed on molecules that are directed against post-translationally modified variants of the Aβ peptide, an emerging approach for development of new antibody molecules.