Dendritic spine head diameter predicts episodic memory performance in older adults.

Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing ß amyloid plaque scores, neurofibrillary tangle pathology, and sex. These findings support the emerging hypothesis that, in the temporal cortex, synapse strength is more critical than quantity for memory in old age.

Alzheimer's Disease Neuropathological Change in Aged Non-Primate Mammals.

Human brain aging is characterized by the production and deposition of ß-amyloid (Aß) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aß is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aß pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aß deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aß deposition is the most common Alzheimer's disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.

Sequence of Molecular Events in the Development of Alzheimer's Disease: Cascade Interactions from Beta-Amyloid to Other Involved Proteins.

Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women?

Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Predicting Brain Amyloid Status Using the National Institute of Health Toolbox (NIHTB) for Assessment of Neurological and Behavioral Function.

BACKGROUND: Amyloid-beta (Aß) plaque is a neuropathological hallmark of Alzheimer's disease (AD). As anti-amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility. OBJECTIVE: To predict brain amyloid status utilizing machine learning approaches in the Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) study. DESIGN: ARMADA is a multisite study that implemented the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive ability levels (normal, mild cognitive impairment, early-stage dementia of the AD type). SETTING: Participants across various sites were involved in the ARMADA study for validating the NIHTB. PARTICIPANTS: 199 ARMADA participants had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers). MEASUREMENTS: We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity. RESULTS: The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 - 0.76, Sensitivity 0.50, Specificity 0.88) on the held-out test set; higher than the LASSO model (0.68 (95% CI:0.68 - 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words-in-noise test (hearing), pattern comparison processing speed, odor identification, 2-minutes-walk endurance, 4-meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers. CONCLUSION: Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive cases (i.e., low sensitivity).

CryoET of ß-amyloid and tau within postmortem Alzheimer's disease brain.

A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures1. In Alzheimer's disease, this is characterized by the deposition of ß-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of ß-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. ß-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of ß-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.

Neuroimaging biomarkers and CSF sTREM2 levels in Alzheimer's disease: a longitudinal study.

Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer's disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aß) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aß-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aß-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aß-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aß-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aß and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aß plaque formation and tau aggregate accumulation only in the presence of Aß pathology.

Revisiting the focal role of endostatin and environmental factors in Alzheimer's disease.

Alzheimer's disease (AD) is a condition initiated by the assimilation of ß-amyloid plaques (Aß) and tau tangles, leading to neurodegeneration. It involves frequently cognitive decline as well as memory impairment in patients. Efforts in therapeutic interventions are currently facing challenges in identifying targets within this scaffold that can significantly alter the clinical course for individuals with AD. Moreover, in AD, neurons release a protein called endostatin, which accumulates in Aß plaques and enhances AD. This accumulation of Aß in the triggers a cascade of events leading to synaptic dysfunction, neuroinflammation, and ultimately neuronal death. Environmental factors nowadays increase the risk of AD with prolonged exposure of heavy metals such as copper (Cu), lead (Pb), mercury (Hg), cadmium (Cd), and other pesticides. It has been observed that these factors can cause the aggregation of Aß and tau which initiates the plaque formation and hence leads to enhanced pathogenesis of AD. This review summarizes the interlinking between heavy metals, environmental factors, pesticides, endostatin, and progression of AD has been deliberated with recent findings.

Synthesis of fluorinated curcumin derivatives for detecting amyloid plaques by 19F-MRI.

The most prominent pathophysiological hallmark of Alzheimer's disease is the aggregation of amyloid-ß (Aß) peptides into senile plaques. Curcumin and its derivatives exhibit a high affinity for binding to Aß fibrils, effectively inhibiting their growth. This property holds promise for both therapeutic applications and diagnostic molecular imaging. In this study, curcumin was functionalized with perfluoro-tert-butyl groups to create candidate molecular probes specifically targeted to Aß fibrils for use in 19F-magnetic resonance imaging. Two types of fluorinated derivatives were considered: mono-substituted (containing nine fluorine atoms per molecule) and disubstituted (containing eighteen fluorine atoms). The linker connecting the perfluoro moiety with the curcumin scaffold was evaluated for its impact on binding affinity and water solubility. All mono-substituted compounds and one disubstituted compound exhibited a binding affinity toward Aß fibrils on the same order of magnitude as reference curcumin. The insertion of a charged carboxylate group into the linker enhanced the water solubility of the probes. Compound Curc-Glu-F9 (with one L-glutamyl moiety and a perfluoro-tert-butyl group), showed the best properties in terms of binding affinity towards Aß fibrils, water solubility, and intensity of the 19F-NMR signal in the Aß oligomer bound form.

Amyloid-ß peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer's disease with APPdup and Down syndrome.

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-ß (Aß) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aß can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aß and tau pathologies in postmortem brain tissues across cases and Aß peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aß peptides with MS-brain imaging. While intraparenchymal Aß deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aß deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aß deposits in capillaries. Investigation of Aß peptide profiles showed a specific increase in Aßx-37, Aßx-38 and Aßx-40 but not Aßx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aß2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aß peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aß deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aß peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-ß42 over Amyloid Positron Emission Tomography.

BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

The growth rate of senile plaques is determined by the competition between the rate of deposition of free Aß aggregates into plaques and the autocatalytic production of free Aß aggregates.

The formation of amyloid beta (Aß) deposits (senile plaques) is one of the hallmarks of Alzheimer's disease (AD). This study investigates what processes are primarily responsible for their formation. A model is developed to simulate the diffusion of amyloid beta (Aß) monomers, the production of free Aß aggregates through nucleation and autocatalytic processes, and the deposition of these aggregates into senile plaques. The model suggests that efficient degradation of Aß monomers alone may suffice to prevent the growth of senile plaques, even without degrading Aß aggregates and existing plaques. This is because the degradation of Aß monomers interrupts the supply of reactants needed for plaque formation. The impact of Aß monomer diffusivity is demonstrated to be small, enabling the application of the lumped capacitance approximation and the derivation of approximate analytical solutions for limiting cases with both small and large rates of Aß aggregate deposition into plaques. It is found that the rate of plaque growth is governed by two competing processes. One is the deposition rate of free Aß aggregates into senile plaques. If this rate is small, the plaque grows slowly. However, if the rate of deposition of Aß aggregates into senile plaques is very large, the free Aß aggregates are removed from the intracellular fluid by deposition into the plaques, leaving insufficient free Aß aggregates to catalyze the production of new aggregates. This suggests that under certain conditions, Aß plaques may offer neuroprotection and impede their own growth. Additionally, it indicates that there exists an optimal rate of deposition of free Aß aggregates into the plaques, at which the plaques attain their maximum size.

Targeting soluble amyloid-beta oligomers with a novel nanobody.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

[18F]Flotaza for Aß Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology.

BACKGROUND: Brain inflammation contributes significantly to the pathophysiology of Alzheimer's disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aß plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. METHODS: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer's-like amyloid and tau pathologies at early and advanced pathological stages. RESULTS: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aß plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids. CONCLUSIONS: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.

Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer's disease.

BACKGROUND: It is not fully established whether plasma ß-amyloid(Aß)42/Aß40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aß plaque deposition, tau tangle aggregation, and neurodegeneration. METHODS: We recruited 470 older adults and analyzed plasma Aß42/Aß40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aß and tau positron emission tomography imaging. The plasma Aß42/Aß40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aß-PET negative cognitively unimpaired individuals and Aß-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aß42/Aß40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aß plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates. RESULTS: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aß plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aß42/Aß40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aß plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aß42/Aß40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aß42/Aß40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings. DISCUSSION: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.

The Kv7 channel opener Retigabine reduces neuropathology and alleviates behavioral deficits in APP/PS1 transgenic mice.

Hyperexcitability of neuronal networks is central to the pathogenesis of Alzheimer's disease (AD). Pharmacological activation of Kv7 channels is an effective way to reduce neuronal firing. Our results showed that that pharmacologically activating the Kv7 channel with Retigabine (RTG) can alleviate cognitive impairment in mice without affecting spontaneous activity. RTG could also ameliorate damage to the Nissl bodies in cortex and hippocampal CA and DG regions in 9-month-old APP/PS1 mice. Additionally, RTG could reduce the Aß plaque number in the hippocampus and cortex of both 6-month-old and 9-month-old mice. By recordings of electroencephalogram, we showed that a decrease in the number of abnormal discharges in the brains of the AD model mice when the Kv7 channel was opened. Moreover, Western blot analysis revealed a reduction in the expression of the p-Tau protein in both the hippocampus and cortex upon Kv7 channel opening. These findings suggest that Kv7 channel opener RTG may ameliorate cognitive impairment in AD, most likely by reducing brain excitability.

Rotating magnetic field inhibits Aß protein aggregation and alleviates cognitive impairment in Alzheimer's disease mice.

Amyloid beta (Aß) monomers aggregate to form fibrils and amyloid plaques, which are critical mechanisms in the pathogenesis of Alzheimer's disease (AD). Given the important role of Aß1-42 aggregation in plaque formation, leading to brain lesions and cognitive impairment, numerous studies have aimed to reduce Aß aggregation and slow AD progression. The diphenylalanine (FF) sequence is critical for amyloid aggregation, and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings. In this study, we examined the effects of a moderate-intensity rotating magnetic field (RMF) on Aß aggregation and AD pathogenesis. Results indicated that the RMF directly inhibited Aß amyloid fibril formation and reduced Aß-induced cytotoxicity in neural cells in vitro. Using the AD mouse model APP/PS1, RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments, including exploration and spatial and non-spatial memory abilities. Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation, attenuated microglial activation, and reduced oxidative stress in the APP/PS1 mouse brain. These findings suggest that RMF holds considerable potential as a non-invasive, high-penetration physical approach for AD treatment.

ß-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease.

Hyperactivity mediated by synaptotoxic ß-amyloid (Aß) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aß peptides before Aß plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aß binding anticalin protein (Aß-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of ß-amyloidosis. Our results suggest that the sole targeting of Aß monomers is sufficient for the hyperactivity-suppressing effect of the Aß-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aß-anticalin-dependent depletion of naturally secreted Aß monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aß monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.