Thy1-ApoE4/C/EBPß double transgenic mice act as a sporadic model with Alzheimer's disease.

Early onset familial Alzheimer's disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPß double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aß aggregation and neurofibrillary tangles formation in the brain validated by Aß PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPß mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.

Gene-Dose-Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer's Mice.

Alzheimer's disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post-menopausal levels of the pituitary gonadotropin follicle-stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD-like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/- and 3xTg;Fshr-/- mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham-operated 3xTg;Fshr-/- mice were implanted with 17ß-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr-/- mice and, to a lesser extent, in 3xTg;Fshr+/- mice- -thus documenting a clear gene-dose-dependent prevention of hippocampal-dependent spatial memory impairment. At 5 and 10 months, sham-operated 3xTg;Fshr-/- mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10-month-old 3xTg;Fshr-/- mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr-/- mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene-dose-dependent reduction mainly in the amyloid ß40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16-month-old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH-blocking agent for the early prevention of cognitive decline in postmenopausal women.

Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aß40 and Aß42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aß42 (mAß42), mAß40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPß transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAß aggregation as validated by Aß PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.

Protocol for screening α-synuclein PET tracer candidates in vitro and ex vivo.

Alpha-synuclein (α-Syn) positron emission tomography (PET) imaging is a valuable approach for diagnosing and monitoring synucleinopathies-related diseases, such as Parkinson disease. Here, we present a protocol for screening potential α-Syn PET tracers using in vitro and ex vivo approaches. We describe steps for employing recombinant pre-formed fibrils and conducting screening procedures on neuronal models, mouse models, and patients' brain tissue sections to assess the specificity and selectivity of the candidate compounds. For complete details on the use and execution of this protocol, please refer to Xiang et al. (2023).1.

Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase.

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-ß precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-ß and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30-200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood-brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPß/δ-secretase in female mice.

Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR in the hippocampus, to drive AD-like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPß/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPß/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aß and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPß/δ-secretase signalling.

Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPß transgenic mice.

Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPß transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPß transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPß/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPß transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPß transgenic mice.

Zein-Based Nanoparticles Improve the Therapeutic Efficacy of a TrkB Agonist toward Alzheimer's Disease.

The brain-derived neurotrophic factor (BDNF)/TrkB pathway plays a crucial role in neural plasticity and neuronal survival but is often deficient in neurodegenerative diseases like Alzheimer's disease (AD). CF3CN acts as a specific TrkB agonist that displays therapeutic effects in the AD mouse model, but its brain/plasma ratio (B/P ratio) distribution is not satisfactory. To increase its brain exposure, we synthesized several derivatives and employed nanoparticle (NP) formulation to optimize the most potent #2 derivative's in vivo PK profiles. We generated stable #2-loaded zein/lactoferrin composite NPs (#2/zein/LF) using the antisolvent co-precipitation method. In vivo PK studies revealed that nanoencapsulation improved #2's oral bioavailability by approximately 2-fold and significantly enhanced its plasma Cmax and t1/2, but the brain profiles were comparable. Pharmacodynamics showed that #2/zein/LF activates TrkB signaling that phosphorylates asparagine endopeptidase (AEP) T322 and decreases its enzymatic activity, resulting in reduced AEP-cleaved amyloid precursor protein and Tau fragments in the brains of AD mice, correlating with its PK profiles. After 3 months of treatment in 3xTg mice, #2/zein/LF decreased AD pathologies and alleviated cognitive dysfunction. Hence, zein/LF composite nanoencapsulation is a promising drug delivery method for improving the PK profiles of a potential preclinical candidate for treating neurodegenerative diseases.

Treatments with the specific δ-secretase inhibitor, compound 11, promote the regeneration of motor and sensory axons after peripheral nerve injury.

Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase) and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded 4 weeks after nerve transection and repair and 2 weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 h with CP11, neurites were nearly 50% longer than in vehicle-treated controls and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signalling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Spinal cord injury-activated C/EBPß-AEP axis mediates cognitive impairment through APP C586/Tau N368 fragments spreading.

Spinal cord injury (SCI) leads to mental abnormalities such as dementia and depression; however, the molecular mechanism of SCI-induced dementia remains a matter of debate. Asparagine endopeptidase (AEP) mediated dementia by enhancing amyloid plaque and Tau hyperphosphorylation, indicating that it played an important role in neurodegeneration. Here we revealed that SCI stimulated AEP activation in mice with T9 contusion injury. Activated-AEP cleaved APP and Tau, resulting in APP C586 and Tau N368 formations, and consequentially accelerated Aß deposit and Tau hyperphosphorylation, respectively. At 9 months following injury, mice demonstrated a severe deterioration in cognitive-behavioral function, which was corroborated by the presence of accumulated AD-specific pathologies. Surprisingly, activated AEP was found in the brains of mice with spinal cord injury. In contrast, AEP knockout reduced SCI-induced neuronal death and neuroinflammation, resulting in cognitive-behavioral restoration. Interestingly, compared to the full-length proteins, truncated Tau N368 and APP C586 were easier to bind to each other. These AEP-processed fragments can not only be induced to pre-formed fibrils, but also amplified their abilities of spreading and neurotoxicity in vitro. Furthermore, as a critical transcription factor of AEP, C/EBPß was activated in injured spinal cord. Elevated C/EBPß level, as well as microglia population and inflammatory cytokines were also noticed in the cortex and hippocampus of SCI mice. These neuroinflammation pathologies were close related to the amount of Tau N368 and APP C586 in brain. Moreover, administration with the AEP-specific inhibitor, compound #11, was shown to decelerate Aß accumulation, tauopathy and C/EBPß level in both spinal cord and brain of SCI mice. Thus, this study highlights the fact that spinal cord injury is a potential risk factor for dementia, as well as the possibility that C/EBPß-AEP axis may play a role in SCI-induced cognitive impairment.

C/EBPß/AEP Signaling Drives Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPß)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPß/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPß/AEP pathway may serve as a novel therapeutic target for the treatment of AD.

Age-related attenuation of cortical synaptic tagging in the ACC is rescued by BDNF or a TrkB receptor agonist in both sex of mice.

Long-term potentiation (LTP) is a key cellular mechanism for learning and memory, and recent studies in the hippocampus found that LTP was impaired in aged animals. Previous studies of cortical LTP have focused primarily on the homosynaptic plasticity in adult mice, while fewer studies have looked at heterosynaptic plasticity-such as synaptic tagging in aged mice. In the present study, we investigated synaptic tagging in adult and middle-aged mice's anterior cingulate cortex (ACC) using the 64-channel multielectrode dish (MED64) recording system. We found that synaptic tagging was impaired in the ACC of middle-aged male mice as compared to adult mice. Both the network late-phase LTP (L-LTP) and the recruitment of inactive responses were reduced in the ACC of middle-aged male mice. Similar results were found in female middle-aged mice, indicating that there is no gender difference. Furthermore, bath application of brain-derived neurotrophic factor (BDNF) or systemic treatment with newly developed TrkB receptor agonists R13, was shown to rescue both synaptic tagging, and L-LTP, in middle-aged mice. To determine the distribution of synaptic LTP within the ACC, a new visualization method was developed to map the Spatio-temporal variation of LTP in the ACC. Our results provide strong evidence that cortical potentiation and synaptic tagging show an age-dependent reduction, and point to the TrkB receptor as a potential drug target for the treatment of memory decline.

C/EBPß/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPß from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPß/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPß or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPß/AEP-dependent manner. Hence, our studies demonstrate that C/EBPß/AEP pathway is critical for mediating Lewy body pathology progression in PD.

Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson's disease.

Gut dysbiosis contributes to Parkinson's disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.

Preserving cognitive function in patients with Alzheimer's disease: The Alzheimer's disease neuroprotection research initiative (ADNRI).

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease (AD) and associated socioeconomic burdens. Abnormal metabolism of amyloid-ß (Aß) has been proposed as a significant pathomechanism in AD, supported by results of recent clinical trials using anti-Aß antibodies. Nonetheless, the cognitive benefits of the current treatments are limited. The etiology of AD is multifactorial, encompassing Aß and tau accumulation, neuroinflammation, demyelination, vascular dysfunction, and comorbidities, which collectively lead to widespread neurodegeneration in the brain and cognitive impairment. Hence, solely removing Aß from the brain may be insufficient to combat neurodegeneration and preserve cognition. To attain effective treatment for AD, it is necessary to (1) conduct extensive research on various mechanisms that cause neurodegeneration, including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level; (2) identify neuroprotective intervention targets against different neurodegeneration mechanisms; and (3) discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients. The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated, multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD. The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD, with the goal of halting or even reversing cognitive decline.

CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals.

INTRODUCTION: Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer's disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. METHODS: In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aß+], 10 Aß+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aß- individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [18F]-AZD4694 and [18F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. RESULTS: CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aß-, P < 0.001; Aß+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [18F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aß PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. CONCLUSION: The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Fine Particulate Matter Triggers α-Synuclein Fibrillization and Parkinson-like Neurodegeneration.

BACKGROUND: The deposition of α-synuclein (α-Syn) in the brain is the pathological hallmark of Parkinson's disease (PD). Epidemiological data indicate that exposure to fine particulate matter (≤2.5 µm in aerodynamic diameter [PM2.5]) is associated with an increased risk for PD. OBJECTIVE: The aim of this study is to investigate whether PM2.5 has a direct effect on α-Syn pathology and how it drives the risk for PD. METHODS: PM2.5 was added into α-Syn monomers and different cell models to test whether PM2.5 can promote the fibrillization and aggregation of α-Syn. α-Syn A53T transgenic mice and α-Syn knockout mice were used to investigate the effects of PM2.5 on PD-like pathology. RESULTS: PM2.5 triggers the fibrillization of α-Syn and promotes the formation of α-Syn fibrils with enhanced seeding activity and neurotoxicity. PM2.5 also induces mitochondrial dysfunction and oxidative stress. Intrastriatal injection or intranasal administration of PM2.5 exacerbates α-Syn pathology and dopaminergic neuronal degeneration in α-Syn A53T transgenic mice. The detrimental effect of PM2.5 was attenuated in α-Syn knockout mice. CONCLUSIONS: Our results identify that PM2.5 exposure could promote the α-Syn pathology, providing mechanistic insights into how PM2.5 increases the risk for PD. © 2022 International Parkinson and Movement Disorder Society.