Tau Neurofibrillary Tangles Research Articles

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency

BackgroundCreatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized. MethodsCerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aβ40, Aβ42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score. ResultsCSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aβ40 [t(31) = 6.11, p < 0.0001], and Aβ42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = −0.60 [−0.88, 0.005]; Aβ40: ρ = −0.67 [−0.91, −0.12]; Aβ42: ρ = −0.62 [−0.89, −0.02]). ConclusionWe describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aβ40, Aβ42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aβ40 and Aβ42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aβ40, Aβ42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer’s disease

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer’s disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer’s disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

High-fat diet negatively affects brain markers, cognitive behaviors, and noncognitive behaviors in the rTg4510 tau mouse model

Alzheimer's disease (AD) drastically impacts cognitive and noncognitive behaviors in both humans and animal models. Two hallmark proteins in AD, amyloid-β plaques and tau neurofibrillary tangles, accumulate in regions of the brain critical for learning and memory, including the hippocampus. Poor dietary choices have been shown to exacerbate cognitive deficits seen in AD. In this study, we assessed the effects of a high-fat diet (HFD - 60 kcal% fat) on cognitive & noncognitive behaviors as well as on brain markers in the rTg4510 tau mouse model. While all mice learned the Morris Water Maze (MWM) task, it was noted that on the last day of acquisition female tau mice had a significantly higher latency to find the platform than male tau mice (p < 0.01). Mice given the HFD spent significantly less time in the target quadrant than those given a control diet (CD) (p < 0.05). Tau mice showed impaired burrowing (p < 0.05) and nesting behaviors (p < 0.001) compared to WT mice and HFD administration worsened burrowing in tau mice. Tau mice exhibited greater levels of glial fibrillary acidic protein (GFAP) (p < 0.05) and significantly less hippocampal cell density than WT mice (p < 0.001). We observed trends of HFD mice having greater levels of GFAP and greater average tangle size than CD mice. These results highlight the importance of dietary choices, especially in older populations more susceptible to AD and its effects.

Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology.

Alzheimer's disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future.

Amyloid-Lowering Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Numerous biomarker studies have clearly demonstrated that AD has a long asymptomatic phase, with the development of pathology occurring at least 2 decades prior to the development of any symptoms. These pathological changes include a stepwise development of amyloid-β (Aβ) plaques, followed by tau neurofibrillary tangles and subsequently extensive neurodegeneration in the brain. In this review, we discuss the first class of drugs intended to be disease modifying to be approved by the US Food and Drug Administration (FDA) for AD-anti-Aβ monoclonal antibodies-and the scientific rationale with which they were developed.

De Novo Design of a β-Helix Tau Protein Scaffold: An Oligomer-Selective Vaccine Immunogen Candidate for Alzheimer's Disease.

Tau pathology is associated with many neurodegenerative disorders, including Alzheimer's disease (AD), where the spatio-temporal pattern of tau neurofibrillary tangles strongly correlates with disease progression, which motivates therapeutics selective for misfolded tau. Here, we introduce a new avidity-enhanced, multi-epitope approach for protein-misfolding immunogen design, which is predicted to mimic the conformational state of an exposed epitope in toxic tau oligomers. A predicted oligomer-selective tau epitope 343KLDFK347 was scaffolded by designing a β-helix structure that incorporated multiple instances of the 16-residue tau fragment 339VKSEKLDFKDRVQSKI354. Large-scale conformational ensemble analyses involving Jensen-Shannon Divergence and the embedding depth showed that the multi-epitope scaffolding approach, employed in designing the β-helix scaffold, was predicted to better discriminate toxic tau oligomers than other "monovalent" strategies utilizing a single instance of an epitope for vaccine immunogen design. Using Rosetta, 10,000 sequences were designed and screened for the linker portions of the β-helix scaffold, along with a C-terminal stabilizing α-helix that interacts with the linkers, to optimize the folded structure and stability of the scaffold. Structures were ranked by energy, and the lowest 1% (82 unique sequences) were verified using AlphaFold. Several selection criteria involving AlphaFold are implemented to obtain a lead-designed sequence. The structure was further predicted to have free energetic stability by using Hamiltonian replica exchange molecular dynamics (MD) simulations. The synthesized β-helix scaffold showed direct binding in surface plasmon resonance (SPR) experiments to several antibodies that were raised to the structured epitope using a designed cyclic peptide. Moreover, the strength of binding of these antibodies to in vitro tau oligomers correlated with the strength of binding to the β-helix construct, suggesting that the construct presents an oligomer-like conformation and may thus constitute an effective oligomer-selective immunogen.

The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer's Disease.

Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer's disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen.

The novel visual cognitive assessment test correlates well with plasma oligomeric amyloid beta in patients with mild cognitive impairment

AbstractBackgroundOligomeric Amyloid Beta (OAβ), is representative of a soluble, neurotoxic and pathogenic form of Aβ, which has been found to function as upstream drivers of Alzheimer’s Disease pathology (Tolar et al., 2021). It serves as a contributory factor towards the formation of cortical Aβ plaques and neurofibrillary Tau tangles, and has been found to induce oxidative stress, synaptic toxicity and neuroinflammation (Tolar et al., 2021). The pathology culminates in neuronal dysfunction/death and resultant neurodegeneration which has been found to manifest clinically as symptoms of cognitive decline. OAβ has been found to correlate with the severity of cognitive performance, as well as brain volume reduction (An et al., 2017, Wang et al., 2017, Meng et al., 2019, Youn et al., 2019, Babapour Mofrad et al., 2021). Nevertheless, its effect on language neutral cognitive tests ‐ the novel Visual Cognitive Assessment Test (VCAT) developed and validated by our team of neurologist and neuropsychologists; remains to be evaluated (Kandiah et al., 2016, Lim et al., 2018, Low et al., 2020).MethodsA cross‐sectional pilot study was conducted in a cohort of 63 patients, clinically diagnosed with mild cognitive impairment (MCI). The patients underwent cognitive evaluation tests, Multimer Detection System (MDS) based plasma OAβ analysis and MRI based cortical grey matter evaluations (Wang et al., 2017, Youn et al., 2019, Pyun et al., 2021, Vipin et al., 2021). Pearson’s correlation evaluated associations between plasma OAβ, cognitive scores [Mini‐Mental State Examination (MMSE), VCAT] and brain volume measures [Grey Matter Volume (GMV) / Intracranial Volume (ICV)].ResultsIncreasing plasma OAβ expression associated with decreasing, VCAT scores (r = ‐0.291, 95% CI = ‐0.504 to ‐0.044, p = 0.022) and MMSE scores (r = ‐0.272, 95% CI = ‐0.489 to ‐0.024, p = 0.032), in MCI patients (Figure 1A, B). Additionally increasing plasma OAβ expression also associated with decreasing and GMV/ ICV ratio (r = ‐0.264, 95% CI = ‐0.489 to ‐0.007, p = 0.045), in MCI patients (Figure 1C).ConclusionFindings from this study, emphasise on the promising clinical utility of plasma OAβ as a biomarker. Future longitudinal studies will validate these associations across the Alzheimer’s disease spectrum.

Brain regional alternative splicing and clinical traits in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is one of the most complex diseases and is characterized by neuropathological features, including accumulation of beta‐amyloid plaques and tau neurofibrillary tangles. These neuropathological features exhibit heterogeneity across brain regions in different patients, leading to different symptoms. Dysregulation of alternative splicing (AS) has been observed to contribute to neuropathological features in AD; however, their molecular mechanisms via AS remain unclear. Therefore, we aimed to systemically investigate the impact of AS (i.e., exon skipping) on AD‐related neuropathological features (i.e., Braak stage and plaque density) and the functional connections of alternately spliced genes across multiple brain regions in AD patients.MethodWe analyzed RNA‐seq data generated by the MSBB project representing two brain regions: the frontal region (frontal pole; FP, n = 175, inferior frontal gyrus; IF, n = 87) and the temporal (parahippocampal gyrus; PH, n = 93 and superior temporal gyrus; ST, n = 101). The data were mapped to the hg19 reference genome with the STAR aligner and exon skipping rates were estimated as percent spliced in (PSI) by rMATs. Then, we performed a linear regression to evaluate clinical or pathogenic associations between exon PSI levels and the Braak stage and plaque density mean for each brain region, considering sex as a covariate.ResultWe identified 192 and 158 exon skipping (ES) associated with Braak stages in the frontal and temporal regions, respectively. In addition, 863 and 845 events were associated with plaque density. Notably, while the two regions shared only 20% (60 events) of Braak‐associated ES, they coincided in 90% (808 events) of plaque‐associated ES. Enrichment analysis of functional annotations found that frontal‐specific ES associated with Braak stage was enriched in interleukin signaling and the neurodegenerative‐related CDK5 pathway, while temporal‐specific ES was enriched in lipoprotein clearance functional pathways. For plaque density‐associated ES shared between regions, the most significantly enriched pathway was Notch4 signaling, represented for example by SOD2, in which skipping of the functional domain‐encoding exon 4 was associated with plaque mean in both regions.ConclusionThis study provides a landscape of brain region‐dependent AS events and of AD risk genes that contribute to neuropathological features in AD patients.

A Surface-Based Federated Chow Test Model for Integrating APOE Status, Tau Deposition Measure, and Hippocampal Surface Morphometry.

Alzheimer's disease (AD) is the most common type of age-related dementia, affecting 6.2 million people aged 65 or older according to CDC data. It is commonly agreed that discovering an effective AD diagnosis biomarker could have enormous public health benefits, potentially preventing or delaying up to 40% of dementia cases. Tau neurofibrillary tangles are the primary driver of downstream neurodegeneration and subsequent cognitive impairment in AD, resulting in structural deformations such as hippocampal atrophy that can be observed in magnetic resonance imaging (MRI) scans. To build a surface-based model to 1) detect differences between APOE subgroups in patterns of tau deposition and hippocampal atrophy, and 2) use the extracted surface-based features to predict cognitive decline. Using data obtained from different institutions, we develop a surface-based federated Chow test model to study the synergistic effects of APOE, a previously reported significant risk factor of AD, and tau on hippocampal surface morphometry. We illustrate that the APOE-specific morphometry features correlate with AD progression and better predict future AD conversion than other MRI biomarkers. For example, a strong association between atrophy and abnormal tau was identified in hippocampal subregion cornu ammonis 1 (CA1 subfield) and subiculum in e4 homozygote cohort. Our model allows for identifying MRI biomarkers for AD and cognitive decline prediction and may uncover a corner of the neural mechanism of the influence of APOE and tau deposition on hippocampal morphology.

Progressive sleep disturbance in various transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia. The relationship between AD and sleep dysfunction has received increased attention over the past decade. The use of genetically engineered mouse models with enhanced production of amyloid beta (Aβ) or hyperphosphorylated tau has played a critical role in the understanding of the pathophysiology of AD. However, their revelations regarding the progression of sleep impairment in AD have been highly dependent on the mouse model used and the specific techniques employed to examine sleep. Here, we discuss the sleep disturbances and general pathology of 15 mouse models of AD. Sleep disturbances covered in this review include changes to NREM and REM sleep duration, bout lengths, bout counts and power spectra. Our aim is to describe in detail the severity and chronology of sleep disturbances within individual mouse models of AD, as well as reveal broader trends of sleep deterioration that are shared among most models. This review also explores a variety of potential mechanisms relating Aβ accumulation and tau neurofibrillary tangles to the progressive deterioration of sleep observed in AD. Lastly, this review offers perspective on how study design might impact our current understanding of sleep disturbances in AD and provides strategies for future research.

Tau seeds occur before earliest Alzheimer’s changes and are prevalent across neurodegenerative diseases

Tau neurofibrillary tangles are a hallmark of Alzheimer’s disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer’s disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer’s-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer’s tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer’s cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer’s disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer’s disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer’s disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.

Xanthine oxidase mediates stress-induced Alzheimer's Disease progression in triple transgenic mice

Alzheimer’s disease (AD) is a progressive disorder associated with oxidative stress and neuroinflammation promoting the deposition of β-amyloid (Aβ) plaques and neurofibrillary tau tangles. Xanthine oxidoreductase (XOR) is a molybdoenzyme responsible for the metabolism of hypoxanthine and xanthine to uric acid. Under inflammatory conditions, high plasma uric acid levels upregulate XOR leading to increased free radical production and promoting cerebrovascular dysfunction. Chronic stress induces cerebrovascular dysfunction and cognitive decline in C57BL/6 mice mediated by XOR, suggesting a link between chronic stress and dementia. However, there is no published data that link XOR and stress to AD pathology and progression. Thus, we tested the hypothesis that chronic stress accelerates AD pathology via the XOR pathway.At 4 months of age, male and female WT (B6129) and triple transgenic (3xTg) AD mice underwent the Unpredictable Chronic Mild Stress (UCMS) model paradigm for 8 weeks. Mice were euthanized at two different time points at 6 and 9 months of age for both control and UCMS groups, and the tissues were harvested. Brain tissue lysates were homogenized, and the total tau and XOR protein was quantified using Western blot and normalized to β-actin. Aβ (1-40) levels in mouse brain homogenates using Aβ ELISA kit. Immunohistochemical staining was performed to study the colocalization of XO and CD-31 in WT and 3xTg coronal sections and analyzed using Fiji ImageJ.UCMS accelerated Aβ(1-40) expression levels (p&lt;0.05) at both 6 and 9 months of age in the 3xTg mice. Tau levels were significantly increased at 6 months of age (p&lt;0.05), but showed no significant differences in protein expression at 9 months of age. XOR levels were significantly upregulated (p&lt;0.05) in the UCMS group at 6 months of age. At 9 months of age, no significant differences were seen in XOR expression across groups indicating that mice taken off from the UCMS protocol had normal levels of XOR due to reduced oxidative stress buildup in the brain. At 6 months of age, a significant decrease in microvessel density (p&lt;0.05) was seen in 3xTg-UCMS mice vs 3xTg controls, with no significant differences seen at 9 months of age, indicating the role of chronic stress on the decline in cerebrovascular functions. Thus, the study establishes the premise that chronic stress mediated by XOR accelerates AD pathology in our early-onset AD model. NIH, NINDS BINP R01 NS117754, Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's Disease: The Role of Xanthine Oxidase This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Insights on benzodiazepines' potential in Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent type of dementia characterized by the deposition of amyloid beta (Aβ) plaque and tau-neurofibrillary tangles (TNTs) in the brain. AD is associated with the disturbances of various neurotransmitters including gamma-aminobutyric acid (GABA). Of note, GABA is reduced in AD, and restoration of GABA effect by benzodiazepines (BDZs) may improve AD outcomes. However, BDZs may adversely affect cognitive functions chiefly in elderly AD patients with sleep disorders. Besides, there is a controversy regarding the use of BDZs in AD. Consequently, the objective of the present review was to disclose the possible role of BDZs on the pathogenesis of AD that might be beneficial, neutral, or detrimental effects on AD. Prolonged use of intermediate-acting BDZ lorazepam exerts amnesic effects due to attenuation of synaptic plasticity and impairment of recognition memory. However, BDZs may have a protective effect against the development of AD by reducing tau phosphorylation, neuroinflammation, and progression of AD neuropathology. On the other side, other findings highlighted that extended use of BDZs was not associated with the development of AD. In conclusion, there are controversial points concerning the use of BDZs and the risk for the progression of AD. Thus, preclinical, and clinical studies are essential in this regard.

Impact of Incidental Synucleinopathy in Mild Cognitive Impairment due to Alzheimer’s Disease (P7-6.003)

<h3>Objective:</h3> We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with faster rate of cognitive decline in the pre-clinical phase compared to MCI controls without mixed pathology. <h3>Background:</h3> The hallmark neuropathologies of Alzheimer’s disease include amyloid plaques and tau neurofibrillary tangles. Recent evidence suggests that incidental co-occurrence of Lewy Bodies (LB), correlates with accelerated disease progression in AD patients. It is unclear whether this effect is also exerted in the pre-dementia phase of AD, in patients with mild cognitive impairment (MCI). <h3>Design/Methods:</h3> 6654 subjects were identified from the National Alzheimer’s Coordinating Center (NACC) database with autopsy-confirmed AD pathology who remained in the MCI, (Albert 2011 criteria), throughout their ADRC annual assessments. 89 subjects had co-incident Lewy Bodies while the remaining 6565 controls lacked any mixed pathology. We utilized a repeated measures longitudinal analysis of multiple cognitive performance markers to determine whether decline in scores occurred at a greater rate in the synucleinopathy subjects. <h3>Results:</h3> For MCI-LB, mean age and education was (72.2± 8.9 and 15.7± 5.8). For MCI+LB subjects mean age and education was (77..9± 7.8 and 16.6± 6.8). 44 MCI +LB subjects and 2555 MCI -LB had complete data for MMSE scores and were included in the corresponding analysis and a subset had complete data for the Weschler Adult Intelligence Scale (WAIS) Digit Symbols test. The rate of decline in overall MMSE scores and WAIS-R Digit Symbols test did not differ between the two groups. <h3>Conclusions:</h3> While mixed LB pathology correlates with a greater rate of cognitive decline in patients with AD, our results do not suggest that co-incident LB accelerates decline in subjects remaining in MCI. To further characterize the effect of mixed pathology on AD disease course, next steps may include investigating whether co-occurrent LB pathology hastens progression to meeting criteria for AD diagnosis. <b>Disclosure:</b> Ms. Shriram has nothing to disclose. Michael Malek-Ahmadi has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care.

Medial Temporal Tau Predicts Memory Decline in Cognitively Unimpaired Elderly (P5-6.011)

<h3>Objective:</h3> Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau PET for predicting longitudinal memory decline in asymptomatic elderly individuals. <h3>Background:</h3> Alzheimer’s disease (AD) can be detected in living people using in vivo biomarkers of amyloid-β (Aβ) and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high affinity positron emission tomography (PET) tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early AD symptoms, such as memory decline, is unclear. <h3>Design/Methods:</h3> In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants from the Translational Biomarkers in Aging and Dementia (TRIAD) study (October 2017-July 2020, follow-up period of 12 months). All participants underwent tau PET with [18F]-MK-6420 and Aβ PET with [18F]-AZD-4694. <h3>Results:</h3> There were 111 eligible participants who were chosen based on the availability of Aβ PET, tau PET, magnetic resonance imaging (MRI), and APOEɛ4 genotyping. Among these participants, the mean (SD) age was 70.1 (8.6) years; 20 (18%) were tau PET positive and 71 of 111 (63.9%) were women. A significant association between baseline Braak I-II [18F]-MK-6240 SUVR positivity and change in composite memory score was observed at the 12 month follow-up, after correcting for age, sex, and years of education (Logical Memory and RAVLT, standardized beta = −0.52 (−0.82−0.21), p &lt; 0.001, for dichotomized tau PET and −1.22 (−1.84−(−0.61)), p &lt; 0.0001, for continuous tau PET). Moderate cognitive decline was observed for A+T+ over the follow-up period, whereas no significant change was observed for A-T+, A+T- and A-T−, though it should be noted that the A-T+ group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function. <h3>Conclusions:</h3> [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. <b>Disclosure:</b> Miss Kwan has nothing to disclose. Mr. Arfaie has nothing to disclose. Mr. Therriault has nothing to disclose. Dr. Azizi has nothing to disclose. Miss Lussier has nothing to disclose. Mrs. Tissot has nothing to disclose. Dr. Chamoun has nothing to disclose. Dr. Bezgin has nothing to disclose. Dr. Servaes has nothing to disclose. Miss Stevenson has nothing to disclose. Ms. Rahmouni has nothing to disclose. Miss Pallen has nothing to disclose. The institution of Dr. Rosa Neto has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk.

Regulation of USP25 by SP1 Associates with Amyloidogenesis.

Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down's syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer's disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. The transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student's t-test or one-way ANOVA were applied or statistical analysis. The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis.

Exploring the therapeutic efficacy of Chlorella pyrenoidosa peptides in ameliorating Alzheimer's disease

Alzheimer's disease (AD) is one of the neurodegenerative disorders, the hallmarks of which include deposits of extracellular beta-amyloid (Aβ) as well as intracellular tau neurofibrillary tangles (NFTs) tangles. With disease progression, neuronal apoptosis combined with cerebral atrophy occurs, leading to cognitive impairment and long-term memory loss. Recently, Chlorella species have been identified as a functional food and are being explored for the prevention of various diseases widely studied to prevent or treat many neurodegenerative diseases. Hence, we for the first time investigated the neuroprotective effects of Chlorella pyrenoidosa short-chain peptides (CPPs) i.e. <1 kDa, 1–3 kDa, 3–10 kDa, and >10 kDa on the in vitro and in vivo neuronal injury models. Our in vitro results showed that CPP with a molecular weight of 1–3 kDa and 3–10 kDa could elevate the survival rate of Aβ1-42 or l-Glutamic acid-injured N2A cells. These treatments also inhibited Aβ and tau NFTs in N2A cells and prevented progressive neuronal cellular damage by suppressing inflammatory cytokines such as PGE2, iNOS, IL-6, TNF-α, COX-2, IL-1β, TGF-β1, and NF-κB. Further, our in vivo Aβ1-42-induced AD mice model demonstrated that 1–3 kDa or 3–10 kDa CPP could improve spatial cognition and learning memory. We also observed a decreased cell loss ratio in CA1-CA3 hippocampal regions. Taken together, our findings imply that CPPs may exert their anti-AD impact through anti-inflammatory, and anti-amyloid activities via reducing APP and tau NFT.

Vascular Dysfunction in Alzheimer's Disease: Alterations in the Plasma Contact and Fibrinolytic Systems.

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. The classical hallmarks of AD include extracellular beta-amyloid (Aβ) plaques and neurofibrillary tau tangles, although they are often accompanied by various vascular defects. These changes include damage to the vasculature, a decrease in cerebral blood flow, and accumulation of Aβ along vessels, among others. Vascular dysfunction begins early in disease pathogenesis and may contribute to disease progression and cognitive dysfunction. In addition, patients with AD exhibit alterations in the plasma contact system and the fibrinolytic system, two pathways in the blood that regulate clotting and inflammation. Here, we explain the clinical manifestations of vascular deficits in AD. Further, we describe how changes in plasma contact activation and the fibrinolytic system may contribute to vascular dysfunction, inflammation, coagulation, and cognitive impairment in AD. Given this evidence, we propose novel therapies that may, alone or in combination, ameliorate AD progression in patients.

Histaminergic neurotransmission in aging and Alzheimer's disease: A review of therapeutic opportunities and gaps.

Alzheimer's disease (AD) is a progressive neurodegenerative disorderfeaturing a brain accumulation of extracellular β-amyloidplaques (Aβ) and intracellular neurofibrillary tautangles (NFTs). Although cognitive decline is a disease-defining symptom of AD, sleep dysfunction, a common symptom often preceding cognitive decline, hasrecently gained more attention as a core AD symptom. Polysomnography and othersleep measures show sleep fragmentation with shortening of N3 sleep togetherwith excessive daytime sleepiness (EDS) and sundowning as the main findings in AD patients. The latter reflects dysfunction of the wake-promoting neurons (WPNs), including histaminergic neurons (HAN) located in thetuberomammillary nucleus (TMN) of the posterior hypothalamus, which projectunmyelinated axons to various parts of the brain. Histamine's role in cognitionand arousal is broadly recognized. Selective targeting of histaminergic subtype-3 and 4 receptors show therapeutic potential in rodent models of AD andaging. Based on PubMed, Scopus, and google scholar databases search, this review summarizes the current knowledge on the histaminergic system in AD and aging, its therapeutic potential in AD, and highlight areas where moreresearch is needed. Animal studies have demonstrated that pharmacological manipulation of histaminergic receptors or histamine supplementation improves cognition in AD models. However, measurements of HA or HA metabolite levels in the human brainand CSF present contradictory reports due to either lack of power or controls for known confounders. Systemic studies including broad age, sex, neuropathological diagnosis, and disease stage are warranted to fill the gap in our current understanding of the histaminergic neurotransmitter/neuromodulator system in humans, especially age-related changes, and therapeuticpotential of histamine in AD-related dysfunction.