ABSTRACT Amyloid‐β (Aβ) is widely regarded as a key initiator of theneurodegenerative cascade in Alzheimer's disease (AD).Studies of pathogenic mutations in the amyloid precursor protein (APP) genehave greatly advanced understanding of Aβ biochemistry, aggregation, anddeposition. One such mutation, Uppsala APP (APPUpp), produces AβUpp42Δ19‐24, whichis highly aggregation‐prone due to a six‐amino‐acid deletion in its central region.In both human APPUpp carriers and the recently developed tg‐UppSwe mouse model, Aβ depositspredominantly consist of the human AβUpp mutant.However, whereas human carriers produce both wild‐type Aβ (Aβwt) and AβUpp, tg‐UppSwe mice express only AβUpp. To better mimic the human condition, weinvestigated the pathological interplay between Aβwt and AβUpp using in vitroco‐aggregation assays and in vivo analyses in abitransgenic mouse model generated by crossing tg‐UppSwe with tg‐Swe mice. ELISA, immunohistochemistry, and MALDI mass spectrometry imaging revealed that earlydeposition of AβUpp42Δ19‐24accelerates aggregation and deposition of Aβwt species (Aβwt38, Aβwt40, Aβwt42), likely through a seeding or catalytic mechanism. Notably, bitransgenic mice developed pronounced plaque‐associated gliosisan alteration absent in tg‐UppSwe animals. These findings suggest a synergistic interaction betweenAβUpp and Aβwt that may influence onset, progression, and structural featuresof Aβ plaques in APPUpp mutation carriers.

Alzheimer's disease (AD) affects over 50 million people worldwide and is the sixth leading cause of death in North America with no cure and limited disease-modifying therapies. Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent, as it promotes the survival and synaptic plasticity of glutamatergic and GABAergic neurons in brain regions associated with cognitive and emotive decline in AD, and mice lacking BDNF exhibits hippocampal long-term potentiation (LTP) impairment, reversible with recombinant BDNF. However, the poor blood-brain barrier (BBB) permeability and pharmacokinetic properties of BDNF limit its clinical use. To address these limitations, a BDNF nanocarrier system is designed using a novel BBB-permeable terpolymer (TP). This terpolymer-based nanoparticle system (BDNF-TPN) with optimized physiochemical properties protects BDNF in circulation and enables sufficient neuronal delivery of BDNF and neuron survival following Aβ exposure in vitro. The biodistribution and safety of BDNF-TPN are evaluated via imaging, enzyme-linked immunosorbent assay, hematologic, clinical biochemical, immunotoxicity, and histology tests. Biomarker studies demonstrate BDNF-mediated neuroprotective signaling in an APP transgenic mouse model following intravenous injection of BDNF-TPN with reduced apoptosis and neuron inflammation and increased neuronal survival and synaptic plasticity. Improved hippocampal-dependent contextual learning in APP transgenic Alzheimer's mice is observed as determined by fear-conditioning assay following two months of weekly treatments.

The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier-crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [1⁸F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. Synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.

INTRODUCTION:Amyloid beta oligomers (Aβos) are toxic to synapses and key to the progression of Alzheimer's disease (AD) and amyloid pathology, representing a target for therapeutic strategies. METHODS:Amyloid and small ubiquitin modifier 2 (SUMO2) transgenics were analyzed by electrophysiology and behavioral testing. A recombinant analogue of SUMO2, SBT02, was generated and assessed for brain penetration and the ability to mitigate amyloid pathology. RESULTS:Elevated SUMO2 expression prevents cognitive and synaptic impairment in a mouse model of AD amyloid pathology. Systemic administration of SBT02 resulted in high brain bioavailability and prophylactically halted the progression of AD-associated deficits. SBT02 also restored cognition and synaptic function in late-stage amyloid load. Mechanistically, SUMO2 and SBT02 do not alter amyloid processing or clearance and mitigate synaptotoxicity in the presence of high amyloid loads. DISCUSSION:SBT02 is a promising therapeutic strategy to counteract and reverse the toxic effects of Aβos in AD. HIGHLIGHTS:Genetic overexpression of human SUMO2 prevents the long-term potentiation (LTP) impairments and cognitive deficits in amyloid precursor protein (APP) transgenics without affecting amyloid pathology. A recombinant analogue of human SUMO2, termed SBT02, when administered systemically, displays high brain bioavailability and has no adverse effects at high doses. Prophylactic treatment of APP transgenics with SBT02 prior to the development of amyloid pathology results in the prevention of synaptic and behavioral dysfunction. SBT02 also reverses pre-existing LTP and cognitive impairments when administered to APP transgenics with advanced and severe pathology. SBT02 has no impact on amyloid pathology, indicating a mechanism of action on synaptic resistance to Aβ toxicity.

The presence of α-synuclein pathology in peripheral nervous system neurons is linked to early prodromal, non-motor symptoms in a segment of Parkinson’s disease (PD) patients referred to as “body-first.” These features of the disease suggest a convergence of environmental, genetic, immune and age-related factors within the enteric nervous system as initiating triggers of disease. This review explores the changes in the gut microbiome and intestinal permeability that may drive systemic inflammation and precede neurodegeneration in PD. The pathways leading to the formation of α-synuclein aggregates are explored as well as their role in transneuronal propagation and the spreading of pathology within the brain. Lastly, advances in systemic gene therapy that could be used to target multiple PD-affected organs following systemic injection are highlighted. By integrating insights from molecular biology and clinical research, it may be possible to shed light on the multifactorial etiology of PD and the interconnectedness of the gut and brain, which could lead to novel diagnostic and therapeutic strategies.

SUMOylation is a post-translational modification involving the addition of SUMO isoforms to target proteins and plays a role in various biological processes, including neurodegenerative diseases and ocular pathologies. This study investigates the interaction between SUMO-2 and amyloid (Aβ) peptides, key contributors to Alzheimer's disease, using techniques like cross-linking mass spectrometry, surface plasmon resonance and biolayer interferometry. Data are available via ProteomeXchange with identifier PXD066055. The results show that Aβ1-40 and Aβ1-42 bind more strongly to SUMO-2 than to ubiquitin, with binding driven by specific hydrogen bonds and hydrophobic interactions. SUMO-2 was found to inhibit the conversion of Aβ into β-sheet structures and impede Aβ aggregation. Notably, Aβ competes with SUMO-2 canonical substrates for binding, completely hindering SUMOylation reactions in vitro. Identifying SUMO-2/Aβ1-42 adducts in cellular extracts and live cells further highlights the biological significance of these interactions. Overall, the findings indicate that Aβ peptides impair SUMO-2 function, pointing to the necessity for more research on the implications of SUMOylation in Alzheimer's disease.

SUMOylation is a post-translational modification involving the addition of SUMO isoforms to target proteins and plays a role in various biological processes, including neurodegenerative diseases and ocular pathologies. This study investigates the interaction between SUMO-2 and amyloid (A(3) peptides, key contributors to Alzheimer's disease, using techniques like cross-linking mass spectrometry, surface plasmon resonance and biolayer interferometry. Data are available via ProteomeXchange with identifier PXD066055. The results show that A(31-40 and A(31-42 bind more strongly to SUMO-2 than to ubiquitin, with binding driven by specific hydrogen bonds and hydrophobic interactions. SUMO-2 was found to inhibit the conversion of A(3 into (3-sheet structures and impede A(3 aggregation. Notably, A(3 competes with SUMO-2 canonical substrates for binding, completely hindering SUMOylation reactions in vitro. Identifying SUMO-2/A(31-42 adducts in cellular extracts and live cells further highlights the biological significance of these interactions. Overall, the findings indicate that A(3 peptides impair SUMO-2 function, pointing to the necessity for more research on the implications of SUMOylation in Alzheimer's disease.

We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimer's disease (AD). The full-length CD33 M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and Aβ). This interaction induces CD33 M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33 M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33 MΔ4bp ).

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer's disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer’s pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.

Neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP (amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40 weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20 weeks old toward 40 weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

gamma-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid-beta. The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin-1 (PS1) and Presenilin-2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1- and PS2-gamma-secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK-293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc-PS1-NTF is 5.5-times higher than Myc-PS2-NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1-gamma-secretase, PS2-gamma-secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1- and PS2-specific contributions to substrate processing, and their potential influence in AD pathogenesis.

IntroductionAbnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer’s disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau deposits primarily affect neurons, but evidence indicates that glial cells may also be affected and contribute distinctively to disease progression. Cells can respond to toxic insults by orchestrating global changes in posttranslational modifications of their proteome. Previous studies suggest that SUMOylation, a posttranslational modification consisting of conjugation of SUMO (Small ubiquitin-like modifier) to target proteins, was decreased in the hippocampus of AD patients and in animal model of AD compared with controls. This decrease in SUMOylation was correlated with increased Tau pathology and cognitive decline. Other studies have reported increased levels of SUMO in AD brains. The goal of our study was to evaluate whether SUMO conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant TauP301L, in neurons and in glial cells.MethodsWe used viral approaches to express mutant TauP301L and SUMO2 in the hippocampus of wild-type mice. We assessed Tau distribution by immunostaining and Tau aggregation by insolubility assays followed by western blotting. We assessed neuronal toxicity and performed cell count and shape descriptor analyses on astrocytes and microglial cells.ResultsWe found that mutant TauP301L, when expressed exclusively in neurons, is toxic not only to neurons but also to glial cells, and that SUMO2 counteracts TauP301L toxicity in neurons as well as in glia.DiscussionOur results uncover an endogenous neuroprotective mechanism, whereby SUMO2 conjugation reduces Tau neuropathology and protects against toxic effects of Tau in glial cells.

Finding effective disease-modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well-characterized mouse model of Alzheimer's disease. The application of brain-penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid β plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging-based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid β. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease-modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

INTRODUCTION Extracellular vesicles (EVs) have been implicated in the spread of neuropathology in Alzheimer's disease (AD), but their involvement in behavioral outcomes linked to AD remains to be determined. METHODS EVs isolated from post mortem brain tissue from control, AD, or frontotemporal dementia (FTD) donors, as well as from APP/PS1 mice, were injected into the hippocampi of wild-type (WT) or a humanized Tau mouse model (hTau/mTauKO). Memory tests were carried out. Differentially expressed proteins in EVs were assessed by proteomics. RESULTS Both AD-EVs and APP/PS1-EVs trigger memory impairment in WT mice. We further demonstrate that AD-EVs and FTD-EVs carry Tau protein, present altered protein composition associated with synapse regulation and transmission, and trigger memory impairment in hTau/mTauKO mice. DISCUSSION Results demonstrate that AD-EVs and FTD-EVs have negative impacts on memory in mice and suggest that, in addition to spreading pathology, EVs may contribute to memory impairment in AD and FTD. HIGHLIGHTS Aβ was detected in EVs from post mortem AD brain tissue and APP/PS1 mice. Tau was enriched in EVs from post mortem AD, PSP and FTD brain tissue. AD-derived EVs and APP/PS1-EVs induce cognitive impairment in wild-type (WT) mice. AD- and FTD-derived EVs induce cognitive impairment in humanized Tau mice. Proteomics findings associate EVs with synapse dysregulation in tauopathies.

Tau oligomers (oTau) secreted by neurons and astrocytes are linked to the propagation of pathology and negatively affect neuronal activity and viability. oTau-mediated synaptic loss leads to cognitive deficits and manifests the clinical outcomes of Alzheimer’s disease and related tauopathies. Small Ubiquitin-like MOdifier (SUMO) proteins regulate multiple cellular events and SUMOylation plays pivotal roles in synaptic biology. Changes in SUMO conjugation and function are also linked to AD and related neurodegenerative disorders such as Huntington’s and Parkinson’s disease. The goal of this investigation is to determine the impact of the two main SUMO isoforms, SUMO1 and SUMO2, on oTau related synaptotoxicity. SUMO1 and SUMO2 transgenic mice were generated with expression regulated by the neuron-specific prion cos-tet promoter. These in vivo models were used to generate double transgenic mice expressing human SUMO proteins and P301S mutant Tau. Changes in synaptic density and activity and the effects of oTau pathology were investigated with respect to cognitive deficits and long term potentiation (LTP). Elevated expression of human SUMO1 lead to impaired synaptic development and increased tau aggregation. SUMO1 transgenics crossed to Tau mutant mice resulted in an accelerated synaptic loss and a more severe disease phenotype as evidenced by LTP impairments and rapid cognitive decline. Conversely, SUMO2 conjugation levels were decreased in the presence of oTau and phospho-tau pathology indicating a down-regulation of its function. Enhanced SUMO2 expression in a mouse model of Tau pathology reversed this process and resulted in a significant reduction in oTau-mediated synaptotoxicity and the associated LTP and cognitive impairments. Cumulatively, our findings indicate that SUMO1 negative impacts and exacerbates oTau-related synaptic dysfunction. In contrast, SUMO2 confers substantial neuroprotection and represents a potential therapeutic avenue to counteract oTau-induced synaptotoxicity in AD.

Aluminum has long been recognized as highly toxic to the nervous system. Aluminum is also essential to the welfare of advanced civilizations. Not only have aluminum compounds been widely used for water treatment, food preservation, and pharmaceuticals, but the metal is also increasingly important in numerous industrial applications. The long-accepted commercial use of aluminum and its compounds has led to considerable resistance to investigating the possible role of aluminum in human disease. Indeed, the complex chemistry of aluminum, the slow accumulation in nervous tissues, and the delayed toxic expression of this element have compounded the difficulty in assigning a precise role in human disease. However, increasing evidence, accumulated in the last five years, has raised important public health concerns regarding excess aluminum exposure in some segments of the population.

SummaryAbnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer’s disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD), which can be caused by mutations of Tau. Mutated and pathological Tau can undergo a range of post-translational modifications (PTMs) that might trigger or modulate disease pathology. Recent studies indicate that modification of wild type Tau bySmallubiquitin-likemodifier SUMO isoform 1 (SUMO1) controls Tau hyperphosphorylation and aggregation, suggesting that SUMOylation acts as a central regulator of Tau’s biochemical properties. Besides SUMO1, Tau is modified by SUMO2/3, however the consequences of this modification have not been investigated. Here, using viral approaches on primary hippocampal neurons, transgenic mice expressing mutant Tau and SUMO2, and iPSC-derived neurons from FTD patients, we evaluated whether SUMO2/3 conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, P301S, and R406W variants. We found that mutant forms of Tau are targets of SUMO2/3, and SUMO2/3 conjugation is neuroprotective. Importantly, expression of mutant Tau is accompanied by a significant reduction of SUMO2/3 conjugation levels, and restoring levels of SUMO2 reduces mutant Tau aggregation and phosphorylation in all model systems Furthermore, overexpression of SUMO2 restores levels of pre- and post-synaptic markers, associated with a complete rescue of the LTP and memory deficits in transgenic mice expressing mutant Tau. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation to detoxify Tau through PTM-based approaches.

Developing effective disease-modifying treatment for Alzheimer’s disease (AD) remains a tremendous challenge due to its multifactorial nature involving multiple pathologic signaling pathways in addition to ineffective drug delivery through the blood-brain barrier (BBB). 1 With this in mind our group has developed multifunctional bioreactive nanoparticles (Ab-TP-MDNPs), consisting of anti-amyloid β antibody (Ab) linked to brain-penetrating terpolymer (TP) and manganese dioxide (MnO 2 ) nanoparticles (MDNPs), that are shown to reduce oxidative stress in AD brains. 2 Given the early occurrence of oxidative stress, hypoxia, and vascular dysfunction in AD brains, 3,4 we investigated the therapeutic effects of Ab-TP-MDNPs on reducing neuroinflammation and vascular dysfunction in an AD mouse model. A transgenic mouse model of AD (TgCRND8 species) and wildtype littermates (WT) were treated with intravenous (i.v.) injection of Ab-TP-MDNPs (twice/week, 100 µmol Mn/kg b.w.) or vehicle for 2-weeks. Oxidative and inflammatory biomarkers were examined using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Vascular function before and after the treatment was studied via high resolution magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was assessed using FAIR (flow-sensitive alternating inversion recovery) technique. BBB permeability was measured via T1 mapping re-acquisition prior to and following i.v. injection of gadolinium-diethylenetriamine penta-acetate (Gd-DTPA) at 1.2 mmol/kg Ab-TP-MDNPs treatment significantly decreased inflammatory cytokines and activation of microglia and astrocytes markers (reactive microglia: hippocampus by 69% and cortex by 59%, reactive astrocytes: hippocampus by 32% and cortex by 33%). In addition, Ab-TP-MDNPs treatment improved CBF (cortex by 19% and subcortex by 35%) and vessel leakage by 29% in the cortex of AD mouse brains. Ab-TP-MDNPs treatment reduced neuroinflammation and vascular dysfunction in an AD mouse model. These findings suggest a new multimodal strategy for AD treatment and encourage further development of such approach for complex neurologic diseases. Reference: 1.Panza F, Lozupone M, Logroscino G, Imbimbo BP. Nature Reviews Neurology . 2019;15(2):73-88. 2.He C, Ahmed T, Abbasi AZ, et al. Nano Today . 2020;35:100965. 3.Sweeney MD, Montagne A, Sagare AP, et al. Alzheimer’s & Dementia . 2019;15(1):158-167. 4.Nortley R, Korte N, Izquierdo P, et al. Science . 2019:eaav9518.