Explainable AI and transformer models: Unraveling the nutritional influences on Alzheimer's disease mortality.

This pioneering study introduces the use of transformer-based machine learning models and explainable AI approaches to explore the impact of nutrition on Alzheimer's disease (AD) mortality. Using data from the Third National Health and Nutrition Examination Survey (Nhanes iii 1988 to 1994) and the NHANES III Mortality-Linked File (2019) databases, we investigate the intricate relationship between various nutritional factors and AD mortality. Our approach features a novel application of transformer models, which are then benchmarked against established methods like random forests and support vector machines. This comparison not only underscores the strengths of transformer models in handling complex medical datasets but also highlights their potential for providing deeper insights into disease progression. Key findings, such as the significant roles of Platelet distribution width in AD mortality in transformer and Serum Vitamin B12 in random forest, are enhanced by the use of Explainable Artificial Intelligence (XAI), particularly the Shapley Additive Explanations (SHAP) and the integrated gradient methods. This study serves as a vital step forward in applying advanced AI techniques to medical research, offering new perspectives in understanding and combating Alzheimer's Disease.

Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology.

BACKGROUND: Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer's disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aß) pathology of speech acoustics measured over multiple assessments in a remote setting. METHODS: Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aß-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2-3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aß-pathology, using linear regression models, adjusted for age, sex and education. RESULTS: The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aß-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aß-negative individuals, although this effect lost significance after correction for multiple testing. CONCLUSION: Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aß-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.

Characterization of white matter hyperintensities in Down syndrome.

INTRODUCTION: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored. METHODS: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume. RESULTS: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes. DISCUSSION: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks. HIGHLIGHTS: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas.

Amyloid PET disclosure in subjective cognitive decline: Patient experiences over time.

INTRODUCTION: We disclosed amyloid positron emission tomography (PET) results in individuals with subjective cognitive decline (SCD) and studied patient experiences and outcomes over a 6-month period. METHODS: Fifty-seven participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (66 ± 8 years, 21 [37%] F, Mini-Mental State Examination 29 ± 1, 15 [26%] amyloid positive [A+]) completed questionnaires 1 week prior (T0), 1 day after (T1), and 6 months after amyloid PET disclosure (T2). Questionnaires addressed patient-reported experiences and outcomes. RESULTS: Independent of amyloid status, participants were satisfied with the consultation (scale 1-10; 7.9 ± 1.7) and information provided (scale 1-4; T1: 3.3 ± 0.9, T2: 3.2 ± 0.8). After 6 months, A+ participants reported more information needs (45% vs. 12%, p = 0.02). Independent of amyloid status, decision regret (scale 1-5; A+: 1.5 ± 0.9, A-: 1.4 ± 0.6, p = 0.53) and negative emotions (negative affect, uncertainty, anxiety) were low (all p > 0.15 and Pinteraction > 0.60). DISCUSSION: Participants with SCD valued amyloid PET disclosure positively, regardless of amyloid status. The need for information after 6 months, which was stronger in A+ individuals, underscores the importance of follow-up. HIGHLIGHTS: Participants with subjective cognitive decline (SCD) positively valued amyloid positron emission tomography (PET) disclosure. Participants with SCD experienced low levels of decision regret. We did not observe an increase in negative emotions. After 6 months, amyloid-positive individuals wanted more information.

Machine and deep learning algorithms for classifying different types of dementia: A literature review.

The cognitive impairment known as dementia affects millions of individuals throughout the globe. The use of machine learning (ML) and deep learning (DL) algorithms has shown great promise as a means of early identification and treatment of dementia. Dementias such as Alzheimer's Dementia, frontotemporal dementia, Lewy body dementia, and vascular dementia are all discussed in this article, along with a literature review on using ML algorithms in their diagnosis. Different ML algorithms, such as support vector machines, artificial neural networks, decision trees, and random forests, are compared and contrasted, along with their benefits and drawbacks. As discussed in this article, accurate ML models may be achieved by carefully considering feature selection and data preparation. We also discuss how ML algorithms can predict disease progression and patient responses to therapy. However, overreliance on ML and DL technologies should be avoided without further proof. It's important to note that these technologies are meant to assist in diagnosis but should not be used as the sole criteria for a final diagnosis. The research implies that ML algorithms may help increase the precision with which dementia is diagnosed, especially in its early stages. The efficacy of ML and DL algorithms in clinical contexts must be verified, and ethical issues around the use of personal data must be addressed, but this requires more study.

Analysis of individual alpha frequency in a large cohort from a tertiary memory center.

BACKGROUND AND PURPOSE: Precise and timely diagnosis is crucial for the optimal use of emerging disease-modifying treatments for Alzheimer disease (AD). Electroencephalography (EEG), which is noninvasive and cost-effective, can capture neural abnormalities linked to various dementias. This study explores the use of individual alpha frequency (IAF) derived from EEG as a diagnostic and prognostic tool in cognitively impaired patients. METHODS: This retrospective study included 375 patients from the tertiary Memory Clinic of IRCCS San Raffaele Hospital, Milan, Italy. Participants underwent clinical and neuropsychological assessments, brain imaging, cerebrospinal fluid biomarker analysis, and resting-state EEG. Patients were categorized by amyloid status, the AT(N) classification system, clinical diagnosis, and mild cognitive impairment (MCI) progression to AD dementia. IAF was calculated and compared among study groups. Receiver operating characteristic (ROC) analysis was used to calculate its discriminative performance. RESULTS: IAF was higher in amyloid-negative subjects and varied significantly across AT(N) groups. ROC analysis confirmed IAF's ability to distinguish A-T-N- from the A+T+N+ and A+T-N+ groups. IAF was lower in AD and Lewy body dementia patients compared to MCI and other dementia types, with moderate discriminatory capability. Among A+ MCI patients, IAF was significantly lower in those who converted to AD within 2 years compared to stable MCI patients and predicted time to conversion (p < 0.001, R = 0.38). CONCLUSIONS: IAF is a valuable tool for dementia diagnosis and prognosis, correlating with amyloid status and neurodegeneration. It effectively predicts MCI progression to AD, supporting its use in early, targeted interventions in the context of disease-modifying treatments.

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism.

INTRODUCTION: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials. METHODS: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering. RESULTS: We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering. DISCUSSION: CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain. HIGHLIGHTS: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09. CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism. Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.

Vitamin B6 Via p-JNK/Nrf-2/NF-κB Signaling Ameliorates Cadmium Chloride-Induced Oxidative Stress Mediated Memory Deficits in Mice Hippocampus.

BACKGROUND: Cadmium chloride (Cd) is a pervasive environmental heavy metal pollutant linked to mitochondrial dysfunction, memory loss, and genetic disorders, particularly in the context of neurodegenerative diseases like Alzheimer's disease (AD). METHODS: This study investigated the neurotherapeutic potential of vitamin B6 (Vit. B6) in mitigating Cd-induced oxidative stress and neuroinflammation-mediated synaptic and memory dysfunction. Adult albino mice were divided into four groups: Control (saline-treated), Cd-treated, Cd+Vit. B6- treated, and Vit. B6 alone-treated. Cd and Vit. B6 were administered intraperitoneally, and behavioral tests (Morris Water Maze, Y-Maze) were conducted. Subsequently, western blotting, antioxidant assays, blood glucose, and hyperlipidemia assessments were performed. RESULTS: Cd-treated mice exhibited impaired cognitive function, while Cd+Vit. B6-treated mice showed significant improvement. Cd-induced neurotoxic effects, including oxidative stress and neuroinflammation, were observed, along with disruptions in synaptic proteins (SYP and PSD95) and activation of p-JNK. Vit. B6 administration mitigated these effects, restoring synaptic and memory deficits. Molecular docking and MD simulation studies confirmed Vit. B6's inhibitory effect on IL-1ß, NRF2, and p-JNK proteins. CONCLUSION: These results highlight Vit. B6 as a safe therapeutic supplement to mitigate neurodegenerative disorders, emphasizing the importance of assessing nutritional interventions for combating environmental neurotoxicity in the interest of public health.

Interpersonal Synchrony in Dance/Movement Therapy: Neural Underpinnings for Individuals with Dementia.

Rising global levels of dementia including Alzheimer's disease call for the treatment of both cognitive and psychosocial deficits of this population. While there is no cure for dementia, the progression can be slowed, and symptoms eased. The positive effects of exercise and dance have been documented as has interpersonal synchrony. Dance/movement therapy uses kinesthetic empathy, attunement, and mirroring to communicate, synchronize, and connect with clients, salient for a population that often struggles with loneliness and isolation. Here I offer a perspective on how dance/movement therapy promotes the social functions and neural underpinning of interpersonal synchrony, possibly providing neuroprotection for this population.

Diagnostic performance of light reflex pupillometry in Alzheimer's disease.

Easily applied diagnostic tools such as digital biomarkers for Alzheimer's disease (AD) are urgently needed due to the recent approval of disease-modifying therapies. We aimed to determine the diagnostic performance of hand-held, quantitative light reflex pupillometry (qLRP) in patients with AD in a proof-of-concept, cross-sectional study. Participants underwent qLRP at a university memory clinic from August 2022 to October 2023. We fitted multivariable logistic regression models with qLRP, sex, and age as predictors evaluated with area under the receiver operating characteristics curve (AUROC). In total, 107 patients with AD, 44 patients with mixed AD and vascular cognitive dysfunction (VCD), 53 patients with dementia with Lewy bodies (DLB), and 50 healthy controls (HCs) were included. Our diagnostic models showed similar discriminatory ability (AUROC range 0.74-0.81) when distinguishing patients with AD from HCs and other dementias. The qLRP seems promising as a bedside digital biomarker to aid in diagnosing AD. Highlights: We demonstrated the diagnostic performance of qLRP in Alzheimer's disease.The diagnostic models were robust in sensitivity analyses.qLRP may assist in the bedside diagnostic evaluation of Alzheimer's disease.

Identification of deregulated lncRNAs in Alzheimer's disease: an integrated gene co-expression network analysis of hippocampus and fusiform gyrus RNA-seq datasets.

Introduction: The deregulation of lncRNAs expression has been associated with neuronal damage in Alzheimer's disease (AD), but how or whether they can influence its onset is still unknown. We investigated 2 RNA-seq datasets consisting, respectively, of the hippocampal and fusiform gyrus transcriptomic profile of AD patients, matched with non-demented controls. Methods: We performed a differential expression analysis, a gene correlation network analysis (WGCNA) and a pathway enrichment analysis of two RNA-seq datasets. Results: We found deregulated lncRNAs in common between hippocampus and fusiform gyrus and deregulated gene groups associated to functional pathways related to neurotransmission and memory consolidation. lncRNAs, co-expressed with known AD-related coding genes, were identified from the prioritized modules of both brain regions. Discussion: We found common deregulated lncRNAs in the AD hippocampus and fusiform gyrus, that could be considered common signatures of AD pathogenesis, providing an important source of information for understanding the molecular changes of AD.

The relationship between hypoxia and Alzheimer's disease: an updated review.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and the most prevalent form of dementia. The main hallmarks for the diagnosis of AD are extracellular amyloid-beta (Aß) plaque deposition and intracellular accumulation of highly hyperphosphorylated Tau protein as neurofibrillary tangles. The brain consumes more oxygen than any other organs, so it is more easily to be affected by hypoxia. Hypoxia has long been recognized as one of the possible causes of AD and other neurodegenerative diseases, but the exact mechanism has not been clarified. In this review, we will elucidate the connection between hypoxia-inducible factors-1α and AD, including its contribution to AD and its possible protective effects. Additionally, we will discuss the relationship between oxidative stress and AD as evidence show that oxidative stress acts on AD-related pathogenic factors such as mitochondrial dysfunction, Aß deposition, inflammation, etc. Currently, there is no cure for AD. Given the close association between hypoxia, oxidative stress, and AD, along with current research on the protective effects of antioxidants against AD, we speculate that antioxidants could be a potential therapeutic approach for AD and worth further study.

Research trends and hotspots for frontotemporal dementia from 2000 to 2022: a bibliometric analysis.

Background: Frontotemporal dementia (FTD) is a neurodegenerative disease with clinical, pathological, and genetic heterogeneity. FTD is receiving increasing attention because it is the second leading cause of early-onset dementia after Alzheimer's disease. This study aimed to analyse the research trends and hotspots of FTD from 2000 to 2022 using bibliometrics. Methods: Papers related to FTD from 2000 to 2020 were systematically searched through the Web of Science Core Collection (WOSCC). Citespace and Vosviewer software were used to visually analyse the retrieved data of countries/regions, institutions, journals, authors, references, and keywords. Microsoft Excel was used to generate the annual publications and growth trends. Results: There were 10,227 papers included in the bibliometric analysis. The annual publication output on FTD has increased significantly from 2000 to 2022, with papers published in 934 academic journals and 87 countries/regions. The Journal of Alzheimer's Disease was the most popular, with 488 papers about FTD. The most productive countries/regions, institutions, and authors are the United States (n = 4,037), the University of California San Francisco (n = 687), and Miller, Bruce L. (n = 427), respectively. The article by Katya Rascovsky and her colleagues published on Brain in 2011 was the most cocited paper, with 625 citations. The research hotspots in this field were the clinical diagnostic criteria, subdivision, and pathological mechanism of FTD, such as tau protein, chromosome 17, progranulin, TDP-43, and C9orf72. Conclusion: The future research direction is based on biomarkers and pathological mechanisms to diagnose and differential diagnose FTD from the aspects of behavior, neuropathology, neuroimaging, and serum markers.

Explore the mechanisms of triterpenoids from Ganoderma lucidum in the protection against Alzheimer's disease via microbiota-gut-brain axis with the aid of network pharmacology.

Ganoderma lucidum (Curtis) P. Karst.(G. lucidum) is a kind of fungi, which also a traditional Chinese medicine used for "wisdom growth" in China. Triterpenoids from G. lucidum (GLTs) are one of the main active ingredients. Based on the strategy of early intervention on Alzheimer's disease (AD) and the inextricable association between disordered gut microbiota and metabolites with AD, this study aimed to explore the mechanisms of GLTs in the protection against AD via microbiota-gut-brain axis with the aid of network pharmacology. In this study, LC-MS/MS was used to identify the main active ingredients of GLTs. Network pharmacology was used to predict the potential target and validated with Caco-2 cell model. D-galactose was used to induce the slow-onset AD on rats. Metabolomics methods basing on GC-MS combined with 16S rRNA sequencing technology was used to carry out microbiota-gut-metabolomics analysis in order to reveal the potential mechanisms of GLTs in the protection of AD. As results, GLTs showed a protection against AD effect on rats by intervening administration. The mechanisms were inextricably linked to GLTs interference with the balance of gut microbiota and metabolites. The main fecal metabolites involved were short-chain fatty acids and aromatic amino acid metabolites.

Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort.

BACKGROUND: Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans. METHODS: In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating. RESULTS: The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes. CONCLUSIONS AND RELEVANCE: Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

Crosstalk between the DNA damage response and cellular senescence drives aging and age-related diseases.

Cellular senescence is a crucial process of irreversible cell-cycle arrest, in which cells remain alive, but permanently unable to proliferate in response to distinct types of stressors. Accumulating evidence suggests that DNA damage builds over time and triggers DNA damage response signaling, leading to cellular senescence. Cellular senescence serves as a platform for the perpetuation of inflammatory responses and is central to numerous age-related diseases. Defects in DNA repair genes or senescence can cause premature aging disease. Therapeutic approaches limiting DNA damage or senescence contribute to a rescued phenotype of longevity and neuroprotection, thus suggesting a mechanistic interaction between DNA damage and senescence. Here, we offer a unique perspective on the crosstalk between the DNA damage response pathway and senescence as well as their contribution to age-related diseases. We further summarize recent progress on the mechanisms and therapeutics of senescence, address existing challenges, and offering new insights and future directions in the senescence field.

Modified Dead-Alive Test for the assessment of semantic and episodic memory performance of older patients with neurocognitive disorder.

The aim of this study is to provide a test that allows for evaluation of both semantic memory (SM) and episodic memory (EM). The study sought to examine psychometric characteristics of the Modified Dead-Alive Test (M-DAT) in patients with neurocognitive disorders and the healthy elderly (HE). The M-DAT consists of 45 names of celebrities who have died in the remote past (15), died in the last five years (15), and are still alive (15), and participants are asked whether they are alive or dead. The M-DAT performances of patients with Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) major neurocognitive disorder due to Alzheimer's Disease (MND-AD) (n = 69) and patients with minor neurocognitive disorder (MiND) (n = 27) who were admitted to a geriatric psychiatry clinic and healthy controls (HC) (n = 29) were compared. Age and level of education were taken as covariates, and an analysis of covariance (ANCOVA) was performed since the MND-AD group was older and less educated. The MND-AD group had lower performance in EM and SM scores of the M-DAT. M-DAT failed to differentiate between MiND and HE. Both subscale scores of the M-DAT were associated with other neuropsychological test performances as well as the level of education. The results suggest that M-DAT is a valid and reliable tool that examines both EM and SM performances. M-DAT is an alternative for the assessment of SM evaluated by verbal fluency or naming tests. Evaluating EM and SM together is an important advantage; however, M-DAT is influenced by education, and the items require updating.

Polygenic hazard score predicts synaptic and axonal degeneration and cognitive decline in Alzheimer's disease continuum.

BACKGROUND: Growth associated protein-43 (GAP-43) and neurofilaments light (NFL) are biomarkers of synaptic and axonal injury, and are associated with cognitive decline in Alzheimer's disease (AD) contiuum. We investigated whether Polygenic Hazard Score (PHS) is associated with specific biomarkers and cognitive measures, and if it can predict the relationship between GAP-43, NFL, and cognitive decline in AD. METHOD: We enrolled 646 subjects: 93 with AD, 350 with mild cognitive impairment (MCI), and 203 cognitively normal controls. Variables included GAP-43, plasma NFL, and PHS. A PHS of 0.21 or higher was considered high risk while a PHS below this threshold was considered low risk. A subsample of 190 patients with MCI with four years of follow-up cognitive assessments were selected for longitudinal analysis . We assessed the association of the PHS with AD biomarkers and cognitive measures, as well as the predictive power of PHS on cognitive decline and the conversion of MCI to AD. RESULTS: PHS showed high diagnostic accuracy in distinguishing AD, MCI, and controls. At each follow-up point, high risk MCI patients showed higher level of cognitive impairment compared to the low risk group. GAP-43 correlated with all follow-up cognitive tests in high risk MCI patients which was not detected in low risk MCI patients. Moreover, high risk MCI patients progressed to dementia more rapidly compared to low risk patients. CONCLUSION: PHS can predict cognitive decline and impacts the relationship between neurodegenerative biomarkers and cognitive impairment in AD contiuum. Categorizing patients based on PHS can improve the prediction of cognitive outcomes and disease progression.

TLR2 immunotherapy suppresses neuroinflammation, tau spread, and memory loss in rTg4510 mice.

In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease.

Microglial modulation as a therapeutic strategy in Alzheimer's disease: Focus on microglial preconditioning approaches.

Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aß) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro-inflammatory mediators. However, microglial activation is not always deleterious. M2-activated microglial cells are considered anti-inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD.