Beta Plaques Research Articles

A neuropathology case report of a woman with Down syndrome who remained cognitively stable: Implications for resilience to neuropathology.

Aging adults with Down syndrome (DS) accumulate Alzheimer's disease (AD) neuropathology, including amyloid beta plaques and neurofibrillary tangles, by age 40. We present findings from an individual with DS who remained cognitively stable despite AD neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Her apolipoprotein E was ε2/ε3 and genome-wide association study data indicated mosaicism. Neuroimaging revealed stable yet elevated amyloid and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies. The participant demonstrated stable cognitive functioning in her 60s, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment. These findings emphasize the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and inform future interventions. Findings from clinical assessments, fluid biomarkers, genotyping, neuroimaging, and neuropathological examinations of an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology are presented. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment, emphasizing the complexity of AD progression in DS.

CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease.

Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2+-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.

Plasma N-terminal tau fragment is an amyloid-dependent biomarker in Alzheimer's disease.

Novel fluid biomarkers for tracking neurodegeneration specific to Alzheimer's disease (AD) are greatly needed. Using two independent well-characterized cohorts (n=881 in total), we investigated the group differences in plasma N-terminal tau (NT1-tau) fragments across different AD stages and their association with cross-sectional and longitudinal amyloid beta (Aβ) plaques, tau tangles, brain atrophy, and cognitive decline. Plasma NT1-tau significantly increased in symptomatic AD and displayed positive associations with Aβ PET (positron emission tomography) and tau PET. Higher baseline NT1-tau levels predicted greater tau PET, with 2- to 10-year intervals and faster longitudinal Aβ PET increases, AD-typical neurodegeneration, and cognitive decline. Plasma NT1-tau showed negative correlations with baseline regional brain volume and thickness, superior to plasma brain-derived tau (BD-tau) and neurofilament light (NfL) in Aβ-positive participants. This study suggests that plasma NT1-tau is an Aβ-dependent biomarker and outperforms BD-tau and NfL in detecting cross-sectional neurodegeneration in the AD continuum. Plasma N-terminal tau (NT1-tau) was specifically increased in the A+/T+ stage. Plasma NT1-tau was positively associated with greater amyloid beta (Aβ) and tau PET (positron emission tomography) accumulations. Higher plasma NT1-tau predicted greater tau burden and faster Aβ increases. Plasma NT1-tau was more related to neurodegeneration than plasma brain-derived tau (BD-tau) and neurofilament light (NfL).

Evidence Suggesting That Alzheimer's Disease May Be a Transmissible Disorder.

Alzheimer's disease (AD) is characterised by progressive neurodegeneration with the formation of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain parenchyma. The causes of AD have been attributed to a combination of age-related changes within the brain as well as genetic, environmental and lifestyle factors. However, a recent study by Banerjee et al. highlights the possibility that AD may be a transmissible disease and that iatrogenic AD could be environmentally acquired, similar to iatrogenic Creutzfeldt-Jakob disease (iCJD). The study reports that contaminated Aβ in cadaver-derived pituitary growth hormone (c-hGH) therapy, which patients received during childhood inoculation, may accidentally transmit into their brains, triggering neurodegeneration and AD onset in older age. Furthermore, corroborating evidence from various animal model studies and human case reports suggests that AD can be potentially transmissible.

Mapping amyloid beta predictors of entorhinal tau in preclinical Alzheimer's disease.

Amyloid beta (Aβ) plaques and hyperphosphorylated tau in the entorhinal regionsare key Alzheimer's disease (AD) markers, but the spatial Aβ pathways influencing tau pathology remain unclear. We applied predictive modeling to identify Aβ standardized uptake value ratio (SUVR) spatial patterns that predict entorhinal tau levels, future hippocampal volume, and Preclinical Alzheimer's Cognitive Composite (PACC) scores at 5-year follow-up. The model was trained on Alzheimer's Disease Neuroimaging Initiative (ADNI) (N=237), incorporating amyloid-PET (positron emission tomography), tau-PET, magnetic resonance imaging (MRI), and cognitive data, and validated on Harvard Aging Brain Study (HABS) (N=276). The model accurately predicted entorhinal tau levels (r=0.48, p<0.0001), future hippocampal volume (r=0.24, p=0.002), and PACC scores (r=0.35, p<0.0001) based on regional Aβ. Aβ in the rostral middle frontal, medial orbitofrontal, and striatal regions predict entorhinal tau levels, future hippocampal volume, and PACC scores, indicating their potential as early biomarkers in AD prediction models. Positron emission tomography (PET) imaging reveals amyloid beta (Aβ) patterns predicting entorhinal tau levels in preclinical Alzheimer's disease (AD). Aβ in medial orbitofrontal, rostral middle frontal, and nucleus accumbens best predicts tau. Aβ distribution in these regions predicts future hippocampal neurodegeneration and cognitive decline. Model validated with Alzheimer's Disease Neuroimaging Initiative (ADNI) and Harvard Aging Brain Study (HABS) data sets, showing robustness and reproducibility. Findings suggest early Aβ patterns can aid in diagnosing AD and guide anti-Aβ therapies.

Alzheimers Disease: Pathological Mechanism and Treatment

Alzheimers disease (AD) is a neurodegenerative condition marked by progressive cognitive decline, impacting the elderly globally. The disease is pathologically defined by the formation of amyloid beta (A) plaques, neurofibrillary tangles (NFTs), mitochondrial dysfunction, abnormal synaptic activity, and immune dysregulation, leading to widespread neuronal death. Current clinical treatments like acetylcholinesterase inhibitors and NMDA receptor antagonists mainly alleviate symptoms but cannot halt disease progression. Research on targeted therapies for A and Tau proteins has gained attention, though clinical trials present challenges. Emerging therapies, including immunization, gene therapy, and stem cell therapy, offer promising prospects. Monoclonal antibodies have shown potential in clearing A plaques, while gamma wave stimulation may reduce amyloid levels. Stem cell therapy aims to enhance neural function through neuronal replacement or regeneration. This review examines ADs primary pathological mechanisms and recent therapeutic progress, emphasizing the potential for significant future breakthroughs as understanding deepens and new treatment strategies develop. By addressing the underlying pathological processes instead of merely alleviating symptoms, these advancements hold promise for more effective AD interventions

Bioactive fraction of Musa balbisiana seed mitigates D-galactose-induced brain aging via SIRT1/PGC-1α/FoxO3a activation and intestinal barrier dysfunction by modulating gut microbiota and core metabolites

Aging is an inevitable biological process, and emerging research has highlighted the potential of dietary and pharmacological interventions to decelerate the trajectory of age-related diseases and prolong the health span. This study evaluates the protective effects of Musa balbisiana seed on healthy aging using D-galactose-induced accelerated aging rats. The results suggested that the bioactive ethyl acetate fraction of Musa balbisiana seed extract (BF) exhibited protective effects against aging-induced oxidative stress by reducing oxidative DNA damage, advanced glycation end-product formation, and malondialdehyde levels while restoring antioxidant and glyoxalase enzyme activities. BF also ameliorated neurodegeneration by decreasing acetylcholinesterase enzyme activity and amyloid beta plaque formation. Histopathological analysis demonstrated the protective effects of BF against brain aging, liver disruption, renal damage, and intestinal barrier dysfunction. BF further restored intestinal permeability by upregulating the tight junctions (zonula occludens 1 and 2, claudin 1,2,3 and 4, and occludin) and mucin (mucin 2 and mucin 5ac) gene expression while downregulating the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α). BF significantly induced the phosphorylation of FoxO3a proteins and upregulated the gene expression of SIRT1, PGC-1α, and TFAM in the hippocampus. Next-generation sequencing (NGS) of 16s rRNA amplicons of fecal metagenomics DNA and metabolites profiling showed that BF intervention restructured the gut microbiota and altered core metabolites related to cholesterol metabolism. Overall, our findings demonstrated the multifaceted protective effects of Musa balbisiana seed against D-galactose-induced aging.

Non-invasive volumetric ultrasound localization microscopy detects vascular changes in mice with Alzheimer's disease.

Alzheimer's Disease (AD) is the most common form of dementia and one of the leading causes of death. AD is known to be correlated to tortuosity in the microvasculature as well as decreases in blood flow throughout the brain. However, the mechanisms behind these changes and their causal relation to AD are poorly understood. Methods: Here, we use volumetric ultrasound localization microscopy (ULM) to non-invasively and quantitatively compare the microvascular morphology and flow dynamics of five wildtype (WT) and five APPNL-G-F Knock-in mice, a mouse model of AD, across a 1cmx1cmx1cm brain volume and in four specific brain regions: the hippocampal formation, thalamus, hypothalamus, and cerebral cortex. Results: Comparisons between groups showed a significant increase in tortuosity, as measured by the Sum of Angles Metric (SOAM), throughout the brain (p < 0.01) and the hypothalamus (p = 0.01), in mice with AD. While differences in mean velocity (p < 0.01) and blood flow (p=0.04) were detected across the whole brain, their effect size was small and no differences were detected in the four selected regions. There was a significant decrease in the linear log relationship between vessel diameter and blood flow, with AD mice experiencing a lower slope than WT mice across the whole brain volume (p = 0.02) and in the hippocampal formation (p = 0.05), a region affected by Amyloid Beta plaques in this mouse model. The AD mice had higher blood flows in smaller vessels and smaller blood flows in larger vessels than the WT mice. Conclusions: This preliminary demonstrates that the imaging technique can be used for non-invasive, longitudinal, volumetric assessment of AD, which may allow for investigation into the poorly understood microvascular degeneration associated with AD through time as well as the development of early diagnostic techniques.

CD4-Derived Double-Negative T Cells Ameliorate Alzheimer's Disease-Like Phenotypes in the 5×FAD Mouse Model.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4+ T cell-derived double-negative T (DNT) cells have shown strong immuno-regulatory properties in both invitro and invivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood. This study's aims were three-fold, to (1) evaluate the efficacy of CD4+ T cell-derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment. We performed tail vein injection of transformed and amplified CD4+ T cell-derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 106 DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation. Through qualitative analysis, we identified 6 main themes. DNT from young wild-type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice. The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus-derived DNT cells. Additionally, CD4+ T cell-derived DNT therapy exhibited anti-inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4+ T cell-derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies.

Pharmacological inhibition of receptor protein tyrosine phosphatase β/ζ decreases Aβ plaques and neuroinflammation in the hippocampus of APP/PS1 mice.

Alzheimer's disease (AD) is a major neurodegenerative disorder that courses with chronic neuroinflammation. Pleiotrophin (PTN) is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ which is upregulated in different neuroinflammatory disorders of diverse origin, including AD. To investigate the role of RPTPβ/ζ in neuroinflammation and neurodegeneration, we used eight-to ten-month-old APP/PS1 AD mouse model. They were administered intragastrically with MY10, an inhibitor of RPTPβ/ζ, at different doses (60 and 90mg/kg) every day for 14days. Treatment with 90mg/kg MY10 significantly reduced the number and size of amyloid beta (Aβ) plaques in the dorsal subiculum of the hippocampus of APP/PS1 mice. In addition, we observed a significant decrease in the number and size of astrocytes in both sexes and in the number of microglial cells in a sex-dependent manner. This suggests that RPTPβ/ζ plays an important role in modulating Aβ plaque formation and influences glial responses, which may contribute to improved Aβ clearance. In addition, MY10 treatment decreased the interaction of glial cells with Aβ plaques in the hippocampus of APP/PS1 mice. Furthermore, the analysis of proinflammatory markers in the hippocampus revealed that MY10 treatment decreased the mRNA levels of Tnfa and Hmgb1. Notably, treatment with MY10 increased Bace1 mRNA expression, which could be involved in enhancing Aβ degradation, and it decreased Mmp9 levels, which might reflect changes in the neuroinflammatory environment and impact Aβ plaque dynamics. These results support the therapeutic potential of inhibition of RPTPβ/ζ in modulating Aβ pathology and neuroinflammation in AD.

Repurposing FDA-Approved Drugs Against Potential Drug Targets Involved in Brain Inflammation Contributing to Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted in the last few decades, only a few drugs have been approved by the FDA for treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need for understanding disease pathogenesis, as well as identifying new targets for further drug discovery. Alzheimer's disease (AD) is known to stem from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD thus make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or 'druggable'. Druggability analysis was conducted using two structure-based methods (i.e., Drug-Like Density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nuclei sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (GPCR that binds C5a), and GABA-A-R (GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found as top inhibitors for more than one protein target. They are C15H14N2O2 and v316 (Paracetamol), used to treat pain/inflammation originally for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigation or clinical trials.

Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease is a progressive and neurodegenerative disease characterized by impairment in emotion, language, memory, and cognitive judgment. There are many factors related to Alzheimer's disease, such as amyloid beta plaques (Aβ) due to impaired metabolism of amyloid precursor protein (APP), tau hyperphosphorylation, and accumulation of neurofibrillary tangles, and disruption of the cholinergic system. Disruption of the cholinergic system responsible for cognitive function and memory processes is one of the important causes of Alzheimer's disease. Therefore, cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitors that maintain choline (acetylcholine and butyrylcholine) levels in the synaptic gap play an important role in the symptomatic treatment of Alzheimer's disease. Numerous studies have been carried out against Alzheimer's disease involving acetylcholinesterase and butyrylcholinesterase inhibitors. However, there are very few drugs (tacrine, rivastigmine, galantamine, and donepezil) approved as cholinesterase inhibitors. Therefore, cholinesterase inhibitors are needed against Alzheimer's disease. This review is focused on using heterocyclic rings that show remarkable cholinesterase inhibitory activity for Alzheimer's disease. In this review, chemical structures and structure-activity relationships of recently reported cholinesterase inhibitors are emphasized. This review will give important ideas to medicinal chemists in the discovery and development of potent cholinesterase inhibitors in their future studies.

Alzheimer’s disease pathologies are pathogen‐driven

AbstractBackgroundAlzheimer’s disease (AD) is diagnosed via postmortem detection of extracellular amyloid beta (Aβ) plaques or oligomers and intracellular hyperphosphorylated tau. These canonical pathologies are key players in AD etiology. A complementary line of research suggests that common human pathogens serve as the initial seeding agents which facilitate the pathologies of AD.MethodLow (n = 8), mild (n = 9), and advanced (n = 10) Alzheimer’s disease brain samples were subjected to expansion microscopy (ExM), a tissue manipulation method which enables the imaging of biological samples at 40nm resolution. For our purposes, we used a novel version of ExM, decrowding expansion pathology (dExPath), which exposes inaccessible protein epitopes to antibody staining while enabling super resolution imaging. Observations from these human brain samples were then modeled using human iPSC neuronal 3D brain organoids and primary rodent cultures.ResultUsing dExPath, we visualized pathogen‐related proteins within our Alzheimer’s disease human brain samples. We discovered a clear colocalization between AD pathologies and pathogen‐derived proteins. When utilizing human brain organoids and rodent cultures as model systems for the human brain, we used pathogen infection to replicate the AD pathologies observed in the AD human brain.ConclusionOur results suggest that (1) neurons exposed to pathogens produce human AD pathologies and (2) AD pathologies may be antimicrobial. With these important roles in mind, our continued research focuses on isolating the mechanisms by which AD pathologies arise in response to common pathogens.

Role of PIM Kinase Inhibitor in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative disorder, is the most prevalent form of senile dementia, causing progressive deterioration of cognition, behavior, and rational skills. Neuropathologically, AD is characterized by two hallmark proteinaceous aggregates: amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) formed of hyperphosphorylated tau. A significant study has been done to understand how Aβ and/or tau accumulation can alter signaling pathways that affect neuronal function. A conserved protein kinase known as the mammalian target of rapamycin (mTOR) is essential for maintaining the proper balance between protein synthesis and degradation. Overwhelming evidence shows mTOR signaling's primary role in age-dependent cognitive decline and the pathogenesis of AD. Postmortem human AD brains consistently show an upregulation of mTOR signaling. Confocal microscopy findings demonstrated a direct connection between mTOR and intraneuronal Aβ42 through molecular processes of PRAS40 phosphorylation. By attaching to the mTORC1 complex, PRAS40 inhibits the activity of mTOR. Furthermore, inhibiting PRAS40 phosphorylation can stop the Aβ-mediated increase in mTOR activity, indicating that the accumulation of Aβ may aid in PRAS40 phosphorylation. Physiologically, PRAS40 is phosphorylated by PIM1 which is a serine/threonine kinase of proto-oncogene PIM kinase family. Pharmacological inhibition of PIM1 activity prevents the Aβ-induced mTOR hyperactivity in vivo by blocking PRAS40 phosphorylation and restores cognitive impairments by enhancing proteasome function. Recently identified small-molecule PIM1 inhibitors have been developed as potential therapeutic to reduce AD-neuropathology. This comprehensive study aims to address the activity of PIM1 inhibitor that has been tested for the treatment of AD, in addition to the pharmacological and structural aspects of PIM1.

Iron–induced, sex‐specific alterations of mitochondrial bioenergetic function and increased amyloid beta plaque size in 5xFAD mice

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal dysfunction leading to decreased memory and cognitive function. AD research has largely focused on the potential pathogenic role of two disease hallmarks: amyloid beta and phosphorylated tau. However, pharmacological interventions targeting these disease hallmarks have met with limited clinical trial success. Thus, other variables may initiate disease etiology prior or contribute to the development of tau and amyloid pathologies. Iron is essential for brain function where its tight regulation aids in neurotransmitter biosynthesis and energy homeostasis. AD patients exhibit high levels of iron in their brain relative to age‐matched, non‐AD patients. However, the potential role of high brain iron levels in AD pathogenesis is unclear.MethodEight‐week‐old male and female C57BL/6 and 5xFAD mice were exposed to standard chow or iron 8 g/kg chow for 8 weeks. Half of the brain from each mouse was used to assess mitochondrial bioenergetic function, with the remaining half quantified for amyloid beta plaque number and size.ResultIron treatment significantly enhanced state 3 (maximum) respiration in male 5xFAD mice, but not in female 5xFAD mice. In contrast, iron treatment increased state 4 respiration in both male and female 5xFAD mice, though the effect in female mice was greater. As a result, mitochondrial respiratory control ratio was greatly impaired in both sexes. Furthermore, iron treatment significantly increased average plaque size in female 5xFAD mice with no effect on male 5xFAD mice, while the total number of plaques were not different in either sex.ConclusionOur data suggest that iron treatment induced sex‐specific alterations of mitochondrial bioenergetic function and amyloid beta plaque size in 5xFAD mice. Future studies will assess the underlying molecular mechanisms driving sex‐specific differences in iron‐induced AD pathology.

A spatial transcriptomics platform for characterizing cellular vulnerability and molecular changes in AD‐affected human brain tissue

AbstractBackgroundAlzheimer’s disease is defined by deposition of pathological proteins in spatially reproducible patterns within the tissue of affected individuals. Prominent pathological protein species found in Alzheimer’s disease are amyloid beta plaques and phospho‐tau tangles, which spread through a succession of brain areas. As this pathology spreads and worsens, it is accompanied by glial reactivity and activation and neuronal loss. Characterization of cell types changing or lost during disease progression and where those changes occur will be important for finding mechanisms of disease onset and progression.MethodsnRNAseq analysis from Alzheimer’s donors was used to determine which cell types are present and what changes in gene expression, if any, can be observed at the highest resolution of cell type identity: the supertype. We mapped these supertypes using highly multiplexed spatial transcriptomics on the same donor set to determine where these supertypes are in the tissue, where vulnerable types are lost at which stages, and whether gene expression changes can be observed in specific types near pathology.ResultWe have found that certain vulnerable cellular supertypes are more likely to be affected early, and a reproducible sequence of neuronal loss follows with increasing pathology. Surprisingly, one of the first neuronal subtypes to be affected are somatostatin inhibitory neurons, followed by L2/3IT excitatory neurons and parvalbumin inhibitory neurons. We have corroborated these results in human donor tissue using spatial transcriptomics to map and characterize loss of abundance of vulnerable cell types. We find that vulnerable neuronal types are predominately localized in supragranular layers.ConclusionSpatial methods are key to relating these neuronal vulnerabilities with pathological protein locations and specific locations within affected tissue. We have adapted spatial profiling and analysis methods to characterize the spatial relationships between specific neuronal types, amyloid plaques, tau tangles, and observed changes in gene expression. These data will offer novel insight into cell and molecular changes occurring at each phase of the disease and may inform the development of promising therapeutic interventions.

Exploration of neuroprotective and cognition boosting effects of Mazus pumilus in Alzheimer's disease model.

Mazus pumilus (MP) an Asian flowering plant, known for various reported pharmacological activities including antioxidant, anti-nociceptive, anti-inflammatory, anticancer, antibacterial, antifungal, and hepatoprotective effects. This study focused on further exploring Mazus pumilus's methanol leaf extract (MPM) for bioactive principles and investigating its neuroprotective and cognition-enhancing potential in Alzheimer's disease models. For the phytochemical screening and identification, TLC, HPLC, and Fourier transform infrared (FTIR) were employed. In-vitro antioxidant potential was assayed by DPPH Free Radical Scavenging method, followed by in-vivo neuroprotective effect of MPM (100, 200, 300 mg/kg) using Wistar-albino rats, sodium azide for induction of AD and rivastigmine as standard. Over 21days, we observed neurobehavioral changes and performed biochemical (GSH, CAT, SOD, and AchE activity) and histopathological evaluations. Results revealed the presence of alkaloids, flavonoids, amino acids, terpenoids, glycosides, sterols, and saponins. HPLC analysis confirmed the presence of gallic acids, sinapic acid, and caffeic acid. DPPH confirmed the antioxidant effect of MPM, which served as a base for its potential neuroprotective activity. Biochemically, oxidative stress markers improved significantly post-treatment, with decreased GSH, SOD, CAT levels, and increased AchE activity, indicating a reversal of AD-induced changes. Behavioral assessments showed improvements in locomotion, memory, spatial learning, and cognition. Histologically, there was a dose-dependent reduction in neurodegenerative features like neurofibrillary tangles and amyloid beta plaques. Hence, this study concluded MPM is a promising candidate for prophylaxis and treatment of behavioral deficits and cognitive dysfunction in Alzheimer's disease.

Navigating the Role and Approach of Gut Microbiota in Addressing Alzheimer's Disease Pathogenesis

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta plaques and tau protein neurofibrillary tangles, leading to cognitive decline. The lack of effective treatments compounds the significant human and financial burdens AD poses. Despite extensive research, the exact mechanisms of the disease remain elusive. Recent studies have shown promise in using anti-Aβ antibodies to reduce amyloid accumulation and slow dementia progression. However, diversifying therapeutic strategies is crucial for making meaningful progress. In recent years, research has increasingly focused on the microbiota-gut-brain axis in AD. Mounting evidence suggests that changes in gut microbiota composition are linked to AD progression, implicating various pathways. Dysregulation of microbiota taxa can trigger systemic inflammation by increasing gut permeability, ultimately leading to neural damage and neurodegeneration. Poor dietary habits and aging exacerbate gut dysbiosis, worsening AD pathology. However, investigations in this area are still in their early stages, with many aspects awaiting exploration and understanding. A thorough comprehension of the complex interactions within the microbiota-AD relationship is essential for refining therapeutic approaches. Interventions targeting gut microbiota, such as dietary adjustments, probiotics, and faecal microbiota transplantation, offer potential as therapeutics. This review highlights the detrimental role of gut dysbiosis in AD, offering insights into enhancing therapeutic avenues for the disease. Graphical abstract: The bidirectional interaction between the brain and the gut through neuroendocrine, immune, and metabolic pathways. Created with BioRender.com

Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation.

Inflammation is emerging as a critical player in the disease progression of Alzheimer's disease (AD) by its interaction with amyloid beta plaques in a feed-forward loop. There is also a decline in the nourishment and enriching neurotrophic factor, brain-derived neurotrophic factor (BDNF), in the brain. Therefore, supplementing the brain with BDNF by gene delivery and delivering the anti-inflammatory agent, cannabidiol (CBD) in this case, to mitigate inflammation-induced disease cascade offers an attractive treatment strategy. To achieve the brain localization of CBD and pBDNF, lipid nanoparticles (LNPs) functionalized with mannose and penetratin were utilized. CBD and pBDNF were successfully encapsulated in the LNPs (more than 80%) with a size less than 180 nm, polydispersity index less than 0.25, and zeta potential of 23 mV. CBD was released from the formulation over a period of a week. The dual-functionalized LNPs demonstrated higher cellular uptake of CBD and expressed a significantly higher amount of BDNF (p-value <0.05) after transfection than their nonmodified counterparts in four brain cell lines, i.e., brain endothelial cells (b.END3), immortalized microglia cells (IMGs), primary astrocytes, and primary neurons. Similarly, the permeation of CBD through the dual-modified LNPs across the in vitro coculture blood-brain barrier model was significantly higher (p-value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta1-42 oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α (p < 0.05) and IL-1β (p < 0.05) in IMG cells. In summary, the penetratin and mannose-functionalized LNPs encapsulating CBD and pBDNF could serve as a promising therapy in AD, requiring further validation in animal models.

Marmosets as model systems for the study of Alzheimer's disease and related dementias: Substantiation of physiological tau 3R and 4R isoform expression and phosphorylation.

Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied. Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404. Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer's disease.