Features Of Alzheimer's Disease Research Articles

Associations of late-life blood pressure with CERAD, Braak, and Thal: Findings from the National Alzheimer's coordinating center neuropathology dataset.

Mid-life high blood pressure (BP) is a risk factor for Alzheimer's disease (AD). CERAD amyloid β (Aβ) plaques, Braak tau neurofibrillary tangles, and Thal Aβ plaque location are major scoring systems for quantifying neuropathological features of AD. We examined the association of late-life systolic BP (SBP) with CERAD, Braak, and Thal in the National Alzheimer's Coordinating Center (NACC) Neuropathology Dataset. Of 1978 participants with data on CERAD, 762 had scores 0-1 (none to sparse) and 1216 had 2-3 (moderate to frequent). Of 1947 with data on Braak, 411 had stages 0-II (normal to mild) and 1536 had III-VI (moderately to very severe). Of 2132 with data on Thal, 438 had phases 0-I, 428 II-III, and 1266 IV-V. Using the mean of the last four SBP before death, SBP was categorized into <120 (references), 120-139, and ≥140 mmHg. Age-sex-adjusted ORs (95% CIs) associated with SBP ≥140 mmHg for CERAD 2-3 and Braak III-VI were 1.37 (1.03, 1.83, P = 0.03) and 1.26 (0.89, 1.78, P = 0.20), respectively. Similar association was observed for Thal II-III and IV-V. These associations essentially remained unchanged after additional adjustment for APOE and Lewy Body pathology. These findings suggest that higher late-life SBP is associated with markers of presence and severity of neuropathological features of AD. Further studies with larger sample sizes are necessary to confirm the findings.

NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.

Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition invivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.

Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer’s disease: a systematic review and network meta-analysis of randomized controlled trials

ObjectiveThe aim of this study was to compare the efficacy and safety of anti-tau protein monoclonal antibodies for Alzheimer’s disease (AD). Tau protein aggregation, a key pathological feature of AD, is closely associated with neurodegeneration and cognitive decline. Targeting tau protein has emerged as a promising therapeutic strategy. By investigating the effects of monoclonal antibodies on cognitive function, disease progression, and overall quality of life in patients with AD, which can provide valuable insights into their potential as a therapeutic option for this devastating neurodegenerative disorder.MethodsThe randomized controlled trials (RCTs) investigating the efficacy of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in Alzheimer’s disease (AD) were systematically searched across PubMed, Embase, Web of Science and Cochrane Library, up to May 2024. The control group included placebo. The efficacy indicators were change in the Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) from baseline until the time of efficacy observation. Statistical analysis was conducted using Stata 14 and RevMan 5.4. The purpose of data processing, including generating network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots, and funnel plots, is to visually summarize and evaluate the relative effectiveness and safety and potential publication bias of multiple interventions. Mean differences (MD) and 95% confidence interval (95%CI) as effect sizes to analyze continuous variables.ResultsThis study encompassed six RCTs involving 2,193 patients. Semorinemab were more effective than placebo in MMSE and ADAS-Cog scores (MDs ranging between 0.52 and 3.21; MDs ranging between 0.17 and 3.30). Placebo showed relatively good efficacy according to SUCRA ranking on change in CDR-SB and ADCS-ADL scores (75.7 and 79.5%). Tilavonemab and Semorinemab exhibited efficacy similar to that of a placebo in the analysis of the two indicators. Tilavonemab showed a lower incidence of AE, SAE, fall, and urinary tract infections than placebo, and the differences were statistically significant. Most safety analysis results showed no statistical difference.ConclusionThe results indicated that anti-tau protein monoclonal antibodies, such as Semorinemab and Tilavonemab, showed promise in terms of efficacy and safety for managing AD. Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388.

Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau-HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.

Senescence Accelerated Mouse-Prone 8: a Model of Neuroinflammation and Aging with Features of Sporadic Alzheimer's disease.

The large majority of Alzheimer's disease (AD) cases are sporadic with unknown genetic causes. In contrast, only a small percentage of AD cases are familial, with known genetic causes. Paradoxically, there are only few validated mouse models of sporadic AD but many of familial AD. Senescence Accelerated Mouse-Prone 8 (SAMP8) mice are a model of accelerated aging with features of sporadic AD. They exhibit a more complete suite of human AD-relevant pathologies than most familial models. SAMP8 brains are characterized by inflammation, glial activation, β-amyloid deposits, and hyperphosphorylated Tau. The excess amyloid deposits congregate around blood vessels leading to vascular impairment and leaky BBBs in these mice. SAMP8 mice also exhibit neuronal cell death, a feature not typically seen in models of familial AD. Additionally, adult hippocampal neurogenesis is decreased in SAMP8 mice and correspondingly, they have reduced cognitive ability. In line with this, hippocampal LTP is significantly compromised in SAMP8 mice. No model is perfect and SAMP8 mice are limited by the lack of clarity about their genomic differences from control SAMR1 (Senescence Accelerated Mouse-Resistant 1) mice although their transcriptomics changes are being revealed. To further complicate matters, multiple substrains of SAMP8 mice have emerged over the years, sometimes making comparisons of studies difficult. Despite these challenges, we argue that SAMP8 mice can be useful for studying AD-relevant symptoms and propose important experiments to strengthen this already useful model.

Alterations in the inflammatory homeostasis of aging-related cardiac dysfunction and Alzheimer's diseases.

Alzheimer's disease (AD) is well known among the elderly and has a profound impact on both patients and their families. Increasing research indicates that ADis a systemic disease, with a strong connection to cardiovascular disease. They share common genetic factors, such as mutations in the presenilin (PS1 and PS2) and the apolipoprotein E (APOE) genes. Cardiovascular conditions can lead to reduced cerebral blood flow and increased oxidative stress. These factors contribute to the accumulation of Aβ plaques and the formation of abnormal tau protein tangles, which are both key pathological features of AD. Additionally, Aβ deposits and abnormal protein responses have been observed in cardiomyocytes as well as in peripheral tissues. The toxic Aβ deposition intensifies damage to the microvascular structure associated with blood-brain barrier disruption and the initiation of neuroinflammation, which may accelerate the onset of neurocognitive deficits and cardiovascular dysfunction. Thus, we discuss the main mechanisms linking AD and cardiac dysfunction to enhance our understanding of these conditions. Ultimately, insights into the brain-heart axis may help us develop effective treatment strategies in the future.

ALZHEIMER'S DISEASE: COMPREHENSIVE INSIGHTS INTO RISK FACTORS, BIOMARKERS, AND ADVANCED TREATMENT APPROACHES

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder primarily affecting individuals over 60. It is a multifactorial disease driven by both modifiable factors, such as lifestyle, diet, and prior health conditions, as well as non-modifiable factors, like age, genetics, and family history. The key pathological features of AD include the buildup of amyloid β plaques and neurofibrillary tangles resulting from hyperphosphorylated tau proteins in the brain. Biomarkers like amyloid β and tau protein levels in cerebrospinal fluid (CSF) and blood are essential for diagnosing and tracking AD progression. Current research focuses on developing drugs targeting multiple aspects of AD pathology, including inflammation, oxidative stress, synaptic dysfunction, and protein accumulation. These treatments aim to slow cognitive decline and neuronal damage. Given the complexity of AD, multi-targeted therapeutic approaches are being explored to enhance treatment efficacy. This review provides an overview of AD risk factors, key biomarkers used for diagnosis, and the latest advances in clinical drug development.

Alzheimer's Disease and Porphyromonas gingivalis: Exploring the Links.

Recent research highlights compelling links between oral health, particularly periodontitis, and systemic diseases, including Alzheimer's disease (AD). Although the biological mechanisms underlying these associations remain unclear, the role of periodontal pathogens, particularly Porphyromonas gingivalis, has garnered significant attention. P. gingivalis, a major driver of periodontitis, is recognized for its potential systemic effects and its putative role in AD pathogenesis. This review examines evidence connecting P. gingivalis to hallmark AD features, such as amyloid β accumulation, tau hyperphosphorylation, neuroinflammation, and other neuropathological features consistent with AD. Virulence factors, such as gingipains and lipopolysaccharides, were shown to be implicated in blood-brain barrier disruption, neuroinflammation, and neuronal damage. P. gingivalis-derived outer membrane vesicles may serve to disseminate virulence factors to brain tissues. Indirect mechanisms, including systemic inflammation triggered by chronic periodontal infections, are also supposed to exacerbate neurodegenerative processes. While the exact pathways remain uncertain, studies detecting P. gingivalis virulence factors and its other components in AD-affected brains support their possible role in disease pathogenesis. This review underscores the need for further investigation into P. gingivalis-mediated mechanisms and their interplay with host responses. Understanding these interactions could provide critical insights into novel strategies for reducing AD risk through periodontal disease management.

Ghrelin Induces Ferroptosis Resistance and M2 Polarization of Microglia to Alleviate Neuroinflammation and Cognitive Impairment in Alzheimer's Disease.

Microglial polarization and ferroptosis are important pathological features in Alzheimer's disease (AD). Ghrelin, a brain-gut hormone, has potential neuroprotective effects in AD. This study aimed to explore the potential mechanisms by which ghrelin regulates the progression of AD, as well as the crosstalk between microglial polarization and ferroptosis.Mouse BV2 microglial cells and male mice were treated with beta-amyloid (Aβ) (1-42) to simulate the AD environment. Microglia ferroptosis was measured by detecting levels of ferroptosis-related proteins (SLC7A11, GPX4, FTL1, and FTH1), metabolic markers (ROS, MDA, GSH, SOD), and observing mitochondrial morphological changes. Microglial polarization was evaluated by measuring levels of inflammatory markers and surface markers. The impact of ghrelin on Aβ1-42-exposed microglia was assessed by coupling with the ferroptosis activator Erastin. Cognitive impairment in AD mice was evaluated through behavioral tests. Tissue staining was applied to determine neuronal damage.In Aβ1-42-exposed microglia, ghrelin upregulated the protein expression of SLC7A11, GPX4, FTL1 and FTH1, reduced ROS and MDA levels, and elevated GSH and SOD levels through the BMP6/SMAD1 pathway. Ghrelin alleviated mitochondrial structural damage. Additionally, ghrelin reduced levels of pro-inflammatory factors and CD86, while increasing levels of anti-inflammatory factors and CD206. Erastin reversed the effects of ghrelin on ferroptosis and phenotypic polarization in Aβ1-42-exposed microglia. In AD mice, ghrelin ameliorated abnormal behavior, neuroinflammation, and plaque deposition. Ghrelin attenuated iNOS/IBA1-positive expression and enhanced Arg-1/IBA1-positive expression in the hippocampus. Ghrelin induces microglial M2 polarization by inhibiting microglia ferroptosis, thereby alleviating neuroinflammation. Our results indicate that ghrelin may serve as a promising potential agent for treating cognitive impairment in AD.

Plasma S100β is a predictor for pathology and cognitive decline in Alzheimer’s disease

BackgroundBlood–brain barrier dysfunction is one characteristic of Alzheimer’s disease (AD) and is recognized as both a cause and consequence of the pathological cascade leading to cognitive decline. The goal of this study was to assess markers for barrier dysfunction in postmortem tissue samples from research participants who were either cognitively normal individuals (CNI) or diagnosed with AD at the time of autopsy and determine to what extent these markers are associated with AD neuropathologic changes (ADNC) and cognitive impairment.MethodsWe used postmortem brain tissue and plasma samples from 19 participants: 9 CNI and 10 AD dementia patients who had come to autopsy from the University of Kentucky AD Research Center (UK-ADRC) community-based cohort; all cases with dementia had confirmed severe ADNC. Plasma samples were obtained within 2 years of autopsy. Aβ40, Aβ42, and tau levels in brain tissue samples were quantified by ELISA. Cortical brain sections were cleared using the X-CLARITY™ system and immunostained for neurovascular unit-related proteins. Brain slices were then imaged using confocal microscopy and analyzed for microvascular diameters and immunoreactivity coverage using Fiji/ImageJ. Isolated human brain microvessels were assayed for tight-junction protein expression using the JESS™ automated Western blot system. S100 calcium-binding protein B (S100β), matrix metalloproteinase (MMP)-2, MMP-9, and neuron-specific enolase (NSE) levels in plasma were quantified by ELISA. All outcomes were assessed for linear associations with global cognitive function (MMSE, CDR) and cerebral atrophy scores by Pearson, polyserial, or polychoric correlation, as appropriate, along with generalized linear modeling or generalized linear mixed-level modeling.ResultsAs expected, we detected elevated Aβ and tau pathology in brain tissue sections from AD patients compared to CNI. However, we found no differences in microvascular diameters in cleared AD and CNI brain tissue sections. We also observed no differences in claudin-5 protein levels in capillaries isolated from AD and CNI tissue samples. Plasma biomarker analysis showed that AD patients had 12.4-fold higher S100β plasma levels, twofold lower NSE plasma levels, 2.4-fold higher MMP-9 plasma levels, and 1.2-fold lower MMP-2 plasma levels than CNI. Data analysis revealed that elevated S100β plasma levels were predictive of AD pathology and cognitive impairment.ConclusionOur data suggest that among different markers relevant to barrier dysfunction, plasma S100β is the most promising diagnostic biomarker for ADNC. Further investigation is necessary to assess how plasma S100β levels relate to these changes and whether they may predict clinical outcomes, particularly in the prodromal and early stages of AD.

Neuronal CD59 isoforms IRIS-1 and IRIS-2 as regulators of neurotransmitter release with implications for Alzheimer’s disease

We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified IRIS-1 and IRIS-2 mRNA in the human brain, though their protein expression and function remained unclear. This study shows the presence of both IRIS-1 and 2 proteins in the human brain, specifically in neurons and astrocytes. In the neuroblastoma cell line (SH-SY5Y), both isoforms are intracellular, and their expression increases upon differentiation into mature neurons. Silencing IRIS-1 and 2 in SH-SY5Y cells reduces the SNARE complex formation, essential for synaptic vesicle exocytosis, leading to a reduction in noradrenaline secretion. Notably, we observed diminished expression of neuronal IRIS-1 and 2 in patients with Alzheimer’s disease (AD) and non-demented individuals with type 2 diabetes (T2D). In SH-SY5Y cells, knockdown of all isoforms of CD59 including IRIS-1 and 2 not only elevates phosphorylated tau but also increases cyclin-dependent kinase 5 (CDK5) expression, known promoter of hyperphosphorylation and accumulation of tau, a key pathological feature of AD. Additionally, we found that prolonged exposure to high glucose or cytokines markedly reduces the expression of IRIS-1 and 2 in SH-SY5Y cells, suggesting a link between AD pathology and metabolic stress through modulation of these isoforms.

HLA is a potent immunoinflammatory target in asymptomatic Alzheimer’s disease

Alzheimer's disease (AD) is a common neurodegenerative disease, neuroinflammation is an early pathological feature of AD. However, the alteration of the immune microenvironment in asymptomatic AD was not fully explained. In this study, we aimed to utilize the transcriptome data of AD patients in public databases to reveal the change of immune microenvironment in asymptomatic AD and screen the potential drug targets. A series of bioinformatics analyses were done, including differentially expressed genes (DEGs) screening, enrichment analysis, PPI network construction, and hub gene identification. Meanwhile, the selected hub genes were validated in APP/PS-1(AD) mice. Importantly, seven enrichment pathways and eight hub genes associated with inflammation were identified in asymptomatic AD. Correspondingly, more hub genes were increased in the hippocampus in AD mice compared to the other four brain regions. Accompanied by the activation of microglia and astrocytes, the inflammatory cytokines were increased in the hippocampus of AD mice. Subsequently, the relationship between HLA-C and inflammation was evaluated in AD mice. HLA-C was correlated with the activation of microglia, and HLA-DRB1 with IL-6 in the hippocampus. Moreover, HLA-C is expressed in the microglia cells and astrocytes. Further, five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone, and Pradaxa) were predicted as the common drug targeting HLA-C and HLA-DRB1 by molecular docking. Taken together, the results revealed the changes in the immune microenvironment of asymptomatic AD and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment.

Distinct CSF α-synuclein aggregation profiles associated with Alzheimer's disease phenotypes and MCI-to-AD conversion.

α-Synuclein (α-Syn) pathology is present in 30-50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear. To explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression. We conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms-Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)-with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD. The ADNI database. A total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD. Pearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β42 (Aβ42). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD. Compared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ42, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD. CSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.

Sleep fragmentation impairs cognitive function and exacerbates Alzheimer's disease-related pathology in a mouse model by disrupting mitochondrial biogenesis.

A large proportion of Alzheimer's disease (AD) patients suffer from various types of chronic sleep disturbances, including sleep fragmentation (SF). In addition, impaired mitochondrial biogenesis is an important feature of AD, but whether it is altered in sleep disorders has not been fully elucidated. Hence, we aimed to investigate the relationship between SF and mitochondrial biogenesis and the possible impact of SF on AD-related pathology. In this study, thirty-six 9-month-old 3xTgAD model mice and thirty-six 9-month-old wild-type (WT) C57BL/6J mice were divided into a control group (6weeks of normal sleep), a SF group (6weeks of SF) and a SF+recovery sleep group (6weeks of SF followed by 2weeks of recovery sleep). Cognitive functions were assessed by behavioural experiments. Mitochondrial structure and function and the activity of a classic mitochondrial biogenesis signalling pathway were investigated using transmission electron microscopy (TEM), reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and Western blotting. Markers of AD-related pathology, including the levels of amyloid β (Aβ) and tau proteins, were assessed by immunofluorescence and Western blotting. The expression of insulin-degrading enzyme (IDE) was assessed by Western blotting. We found that long-term SF impaired the cognitive functions of the mice. In addition, chronic SF reduced the expression of mitochondrial respiratory chain components, the number of mitochondria, the fluorescence intensity of COX-IV, the level of mitochondrial DNA (mtDNA) and the expression of crucial regulators of the AMPK/SIRT-1/PGC-1α signalling pathway in the mouse prefrontal cortex and hippocampus, while recovery sleep could partly abrogate these effects. Moreover, SF reduced the protein level of IDE and increased the Aβ burden and tau hyperphosphorylation. This study demonstrates that chronic SF can negatively regulate the AMPK/SIRT-1/PGC-1α signalling pathway to disrupt mitochondrial biogenesis in the brains of mice, which may subsequently exacerbate AD-related pathology by decreasing the expression of IDE.

PROTEASOME DYSFUNCTION A KEY PATHOLOGIC FEATURE OF ALZHEIMER’S DISEASE MITIGATED BY PROTEASOME ACTIVATORS

Abstract Alzheimer’s Disease (AD) is the leading cause of dementia worldwide, affecting nearly 50 million people and characterized by cognitive decline, β-amyloid plaques, and hyperphosphorylated tau. The failure of numerous clinical trials targeting β-amyloid (Aβ) underscores the need for novel therapeutic strategies. A consistent feature of AD, particularly in the hippocampus, is reduced proteasome activity. This impairment is thought to result from direct inhibition by Aβ or hyperphosphorylated tau, disrupting essential neuronal processes like memory and synaptic plasticity. This study explores the hypothesis that AD-related deficits are driven, in part, by Aβ-induced proteasome dysfunction. We demonstrate that oligomeric Aβ inhibits 20S proteasome activity while destabilizing the 26S proteasome into free 20S units. Treatment with proteasome activators enhances 20S and 26S function, reducing Aβ42-induced toxicity in SK-N-SH cells. In Drosophila overexpressing Aβ42, oral administration of proteasome agonists delayed mortality and restored cognitive function. Similarly, in mouse models, chronic treatment with proteasome activators protected against Aβ42-induced working memory deficits, and acute treatment significantly improved spatial learning deficits in hAPP(J20) mice. Our findings reveal that Aβ exerts dual inhibitory effects on 20S and 26S proteasomes, contributing to AD pathology. Proteasome activation mitigates these deficits, suggesting that enhancing proteasome activity could be a promising therapeutic approach for AD.

A shift towards super-critical brain dynamics predicts Alzheimer’s disease progression

Alzheimer’s disease (AD) is the most common form of dementia with continuum of disease progression of increasing severity from subjective cognitive decline (SCD) to mild cognitive impairment (MCI), and lastly to AD. The transition from MCI to AD has been linked to brain hyper-synchronization, but the underlying mechanisms leading to this are unknown. Here, we hypothesized that excessive excitation in AD disease progression would shift brain dynamics towards supercriticality across an extended regime of critical-like dynamics. In this framework, healthy brain activity during aging preserves operation at near the critical phase transition at balanced excitation-inhibition (E/I). To test this hypothesis, we used source-reconstructed resting-state MEG data from a cross-sectional cohort (N=343) of individuals with SCD, MCI and healthy controls (HC) as well as from a longitudinal cohort (N=45) of MCI patients. We then assessed brain criticality by quantifying long-range temporal correlations (LRTCs) and functional EI (fE/I) of neuronal oscillations. LRTCs were attenuated in SCD in spectrally and anatomically constrained regions while this breakdown was progressively more widespread in MC. In parallel, fE/I was increased in the MCI but not in the SC cohort. Both observations also predicted the disease progression in the longitudinal cohort. Finally, using machine learning trained on functional (LRTCs, fE/I) and structural (MTL volumes) features, we show that LRTCs and f/EI are the most informative features for accurate classification of individuals with SCD while structural changes accurate classify the individuals with MCI. These findings establish that a shift towards super-critical brain dynamics reflects early AD disease progression.Significance StatementThe neuronal mechanisms underlying progression of Alzheimer’s disease (AD) are not well understood. One characteristic feature of AD is brain hyper-synchronization, but the mechanisms leading to this hyper-synchronization have remained unclear. We investigated whether AD dementia progression can be explained in the framework of brain criticality by the shift in individual brain states along an extended regime of critical-like dynamics. We analysed brain criticality with measures of long-range temporal correlations and functional excitation-inhibition balance from source-reconstructed resting-state magnetoencephalography (MEG) data. We show that AD dementia progression is associated with a gradual increase in excitability and a progressive shift towards super-critical brain dynamics.

The analysis of whether CRISPR-Cas9 is the way forward for Alzheimers disease treatment

Alzheimer's disease (AD) is a progressive and irreversible neurological condition which according to WHO affects more than 55 million individuals globally and is the leading cause of dementia and thereby poses a significant burden on healthcare systems worldwide. AD progresses through stages of mild cognitive impairment to severe dementia and is characterised by the accumulation of extracellular amyloid-beta plaques and neurofibrillary tangles concentrated with tau proteins in neocortical structures and the temporal lobe. Gene-editing technology such as the most prevalent CRISPR-Cas9 provides prospects for the treatment of AD by enabling precise modifications of the genetic mutations associated with the disease. This review explores the potential of CRISPR-Cas9 to revolutionise treatment by targeting and rectifying mutated genes but also examines the current state of Alzheimers treatment. This paper examines recent advancements in preclinical studies and highlights the successes in reducing amyloid-beta plaques and tau neurofibrillary tangles, the pathological features of AD. By evaluating current CRISPR-Cas9 research and other treatments for AD, I aim to provide insight into its potential as a transformative gene therapy approach whilst evaluating its limitations.

Identification of high‐performance blood‐based biomarkers for early screening and staging of Alzheimer’s disease by large‐scale plasma proteomic profiling in mild cognitive impairments

AbstractBackgroundEarly detection of Alzheimer's disease (AD), particularly during the mild cognitive impairment (MCI) stage, is crucial for effective intervention and treatment. However, existing diagnostic methods, through cognitive assessments, brain imaging, or cerebrospinal fluid profiling, are subjective, expensive or invasive. We previously showed that the plasma proteome is altered in AD, suggesting the feasibility of utilizing blood biomarkers for AD detection. Therefore, to develop a blood test for early screening and staging of AD, it is important to identify blood biomarkers associated with MCI/early AD and the features of AD progression.MethodWe conducted a comprehensive profiling of the plasma proteome of MCI by measuring 1,160 proteins in a Hong Kong Chinese cohort, to identify novel blood biomarkers for MCI/early AD. We further developed a biomarker panel based on the identified MCI/AD‐associated blood biomarkers and validated its performance in an independent amyloid‐PET‐defined cohort.ResultWe identified 496 proteins that were dysregulated in MCI plasma, and these proteins, involved in different biological processes, exhibited distinct dysregulating patterns with disease progression. We further categorized these proteins into different groups based on their dysregulating patterns. By performing co‐expression network analysis, we identified an 18‐protein panel that captures the profile changes of plasma proteome in MCI and AD. This panel accurately classified MCI (AUC = 0.913‐0.925) and AD (AUC = 0.970‐0.993) in two independent cohorts. Moreover, this panel correlates with cognitive decline and the development of Aβ pathology in the brain, which outperforms some of the existing plasma ATN biomarkers.ConclusionThis study comprehensively profiled the MCI plasma proteome and demonstrates the feasibility of a blood‐based biomarker assay for early detection and staging of MCI and AD, potentially facilitating early screening, monitoring, and intervention in future clinical settings.

Phospholipase D3 (PLD3) Regulates Lysosomal Biogenesis

AbstractBackgroundGenome‐wide association studies suggest mutations in endolysosomal genes are linked to Alzheimer’s disease (AD). Defective lysosomal function has been corroborated as a feature of AD by neuropathological and cell biology studies. PLD3 is a homolog of the phospholipase D family localized to lysosomes. Genetic variants in PLD3 are associated with increased risks for AD. Nevertheless, being a resident lysosomal protein, PLD3’s role in lysosome homeostasis has not been completely characterized. In this study, we conducted studies that combine transcriptomics, proteomics and cell biology to investigate the role of PLD3 in lysosome homeostasis.MethodWe generated PLD3 knockout (KO) SH‐SY5Y cells through the CRISPR/Cas9 approach. To identify the individual genes or gene sets impacted by PLD3 KO, RNA sequencing was performed with RNA isolated from wildtype (WT) and PLD3 KO neurons, followed by differential gene expression and gene set enrichment analyses. To narrow down to the targets that have direct lysosomal relevance, a proteomic study was conducted on the lysosome fraction of lysates from WT and PLD3 KO cells. To characterize lysosome morphology and function, lysosomes in these cells were labeled with Lysotracker or dextrans, followed by imaging, quantification and statistical analysis with CellInsight High Content Analysis platform. Lastly, we also examined the effects of PLD3 on lysosomal biogenesis by immunocytochemistry and Western blot.ResultIn RNA‐Seq analysis, the genes or gene sets relevant to endocytosis, autophagy and lysosomal biogenesis were significantly enriched in PLD3 KO cells. In line with these findings, our proteomic analysis also demonstrated an increase in lysosomal proteins in PLD3 KO cells. PLD3 loss caused an increase in lysosome size and endocytic activity and a decrease in the pH value of lysosomes, but it had no significant impact on lysosome number and positioning. Mechanistically, PLD3 deficiency promoted TFEB‐mediated lysosomal biogenesis.ConclusionPLD3 plays a role in lysosomal biogenesis. As endolysosomal abnormalities are increasingly appreciated as the causal agent for the pathogenesis of AD, this study may position the PLD3 pathway as a therapeutic target for the treatment of AD.

Role of TDP‐43 in dysregulation of cholesterol metabolism and implications for AD

AbstractBackgroundLipid dysregulation is a known feature of Alzheimer’s Disease. Importantly, alterations in lipids pathways affect immune responses in cells like microglia, which have been shown to accumulate cholesterol in both aging and neurodegeneration. Recently, the presence of TDP‐43 inclusions has been linked to increased severity of cognitive impairment in AD patients. While TDP‐43 inclusions are associated primarily with ALS, their presence has been observed in around 57% AD patients. The link between TDP‐43, cholesterol dyshomeostasis and defects in immune responses in the context of AD is yet to be uncovered.MethodMicroglia: Peripheral blood mononuclear cells (PBMCs) are isolated and microbead separation is used to further purify monocytes. These monocytes are cultured with a cytokine cocktail for 10‐14 days to induce differentiation into MDMi (monocyte derived microglia). N = 17 Knockdown screen: Lentivirus mediated shRNA knockdown is used to reduce expression of various genes implicated in AD and ALS, including TREM2, CD33 and TARDBP in MDMi. Functional assays: Cholesterol uptake is measured by using a fluorescence microplate reader and lipid droplets are stained using LipidTox. Gene expression is measured using Fluidigm.ResultTARDBP knockdown resulted in the most significant downregulation of several cholesterol metabolism associated genes, including ABCG1, NPC1, CYP27A1, LXR and SREBP1/2, which are involved in cholesterol uptake, storage and synthesis. The TARDBP knockdown MDMi also had reduced cholesterol uptake and lowered response to LPS stimulation, compared to other gene knockdowns.ConclusionTARDBP plays an important role in the regulation of cholesterol metabolism, specifically cholesterol uptake. The presence of TDP‐43 inclusions in AD may thus contribute to AD pathology through loss of function of TARDBP, causing defects in cholesterol homeostasis which lead to altered microglia function. This also has implications in better understanding Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), a recently characterized type of dementia associated with TDP‐43 proteinopathy.