Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype.

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.

Impact of Mood Disorder History and Bone Health on Cognitive Function Among Men Without Dementia.

BACKGROUND: Poor cognitive function, a major disabling condition of older age, is often considered a prodromal feature of dementia. High mortality and the lack of a cure for dementia have necessitated a focus on the identification of potentially modifiable risk factors. Mental and physical health conditions such as mood disorders and bone loss have been previously linked with poor cognition individually although their combined effect remains largely unknown. OBJECTIVE: Considering the multifactorial nature of dementia pathology, we investigated whether mood disorders, bone health and their interaction are associated with cognitive function in a population-based sample of men. METHODS: Four hundred and forty-two male participants were drawn from the Geelong Osteoporosis Study. Cognitive function was assessed using the CogState Brief Battery, which measured cognitive performance across four domains and was used to compute overall cognitive function. Mood disorders and hip bone mineral density (BMD) were determined using a semi-structured clinical interview and dual-energy X-ray absorptiometry, respectively. RESULTS: Hip BMD (Bcoeff = 0.56, 95% CI: [0.07, 1.05], p = 0.025) but not mood disorder (Bcoeff = -0.50, 95% CI: [-0.20, 0.10], p = 0.529) was associated with overall cognitive function after accounting for potential confounders. Interaction effects were observed between the two exposures (Bcoeff = -1.37, 95% CI: [-2.49, -0.26], p = 0.016) suggesting that individuals without a mood disorder displayed better cognitive performance with increasing BMD, while those with a lifetime history of mood disorder displayed poorer cognitive function with increasing BMD. CONCLUSIONS: These findings highlight the importance of exploring interactions among potentially modifiable health conditions associated with cognitive function.

A plasma protein signature associated with cognitive function in men without severe cognitive impairment.

BACKGROUND: A minimally invasive blood-based assessment of cognitive function could be a promising screening strategy to identify high-risk groups for the incidence of Alzheimer's disease. METHODS: The study included 448 cognitively unimpaired men (mean age 64.1 years) drawn from the Geelong Osteoporosis Study. A targeted mass spectrometry-based proteomic assay was performed to measure the abundance levels of 269 plasma proteins followed by linear regression analyses adjusted for age and APOE ε4 carrier status to identify the biomarkers related to overall cognitive function. Furthermore, two-way interactions were conducted to see whether Alzheimer's disease-linked genetic variants or health conditions modify the association between biomarkers and cognitive function. RESULTS: Ten plasma proteins showed an association with overall cognitive function. This association was modified by allelic variants in genes ABCA7, CLU, BDNF and MS4A6A that have been previously linked to Alzheimer's disease. Modifiable health conditions such as mood disorders and poor bone health, which are postulated to be risk factors for Alzheimer's disease, also impacted the relationship observed between protein marker levels and cognition. In addition to the univariate analyses, an 11-feature multianalyte model was created using the least absolute shrinkage and selection operator regression that identified 10 protein features and age associated with cognitive function. CONCLUSIONS: Overall, the present study revealed plasma protein candidates that may contribute to the development of a blood-based screening test for identifying early cognitive changes. This study also highlights the importance of considering other risk factors in elucidating the relationship between biomarkers and cognition, an area that remains largely unexplored.

Genetic polymorphism in BIN1 rather than APOE is associated with poor recognition memory among men without dementia.

Although several genetic polymorphisms have been linked with the risk of Alzheimer's disease, less is known about their impact on cognitive performance among cognitively healthy individuals. Our aim was to investigate the association of the genetic variant, rs744373 in the bridging integrator 1 gene (BIN1), the strongest genetic risk factor for Alzheimer's disease after the APOE ε4 allele, with different cognitive domains among non-demented older men. Cognitive function was measured using the CogState Brief Battery, which assessed cognitive performance across four domains: psychomotor function, visual attention, recognition memory and working memory. Linear regression analysis revealed that individuals with the BIN1 risk allele performed poorly on the recognition memory task as compared to those without the risk allele. However, this was in contrast with the individuals who harboured the APOE ε4 risk allele as they displayed better performance on the recognition task in comparison to those without the ε4 risk allele. To the best of our knowledge, this is the first study that demonstrates genetic variation in BIN1 to be a better predictor of recognition memory than APOE, which remains the biggest genetic risk factor for Alzheimer's disease.

Depression and bone loss as risk factors for cognitive decline: A systematic review and meta-analysis.

BACKGROUND: Depression is linked to Alzheimer's disease (AD) but it is unclear whether depression is also associated with cognitive decline in the preclinical phase and mild cognitive impairment (MCI). Previous meta-analyses have only investigated AD as an outcome without accounting for individuals showing cognitive decline that does not meet the diagnostic criteria for AD. Other potentially modifiable risk factors such as bone loss have also been less explored and there remains uncertainty around their temporal relationship with cognitive decline. AIMS: To conduct a systematic review and meta-analysis investigating depression and bone loss as risk factors for subsequent cognitive decline. METHODS: A comprehensive search strategy was developed and applied using four databases; MEDLINE Complete, Embase, PsycINFO and CINAHL Complete. The pooled summary effects were estimated as odds ratios with 95% confidence intervals using a random-effects model. The study protocol was registered with PROSPERO (ID: CRD42020159369). RESULTS: A total of 75 longitudinal cohort studies were identified for meta-analysis, of which 70 examined the impact of depression on cognitive decline and five examined the impact of bone loss. Prior exposure to depression was found to be associated with cognitive score reduction (OR 1.33 95% CI 1.17, 1.51), MCI incidence (OR 1.52 95% CI 1.28, 1.79) and AD incidence (OR 1.79 95% CI 1.46, 2.2). Bone loss was also associated with the incidence of AD (OR=1.81 95% CI 1.28, 2.55). CONCLUSIONS: Overall, the results support the hypothesis that depression is associated with subsequent cognitive decline. Bone loss was also found to be associated with AD incidence; however, due to the small number of studies, the results should be viewed with caution.

Decreased cerebrospinal fluid neuronal pentraxin receptor is associated with PET-Aß load and cerebrospinal fluid Aß in a pilot study of Alzheimer's disease.

Multifactorial pathological processes of Alzheimer's disease (AD) begin decades prior to clinical onset. Early identification of patients at risk of developing AD using biomarkers reflecting various aspects of pathogenesis is necessary for prevention and early intervention. Cortical ß-amyloid (Aß) burden assessed by positron emission tomography (PET) or cerebrospinal fluid (CSF) levels of Aß42 are validated biomarkers for early identification. Recently, alterations in levels of neuronal proteins, neuronal pentraxin receptor (NPTXR) and neurofilament light (NfL), in the CSF have emerged as promising AD biomarkers. However, their association with Aß deposition is not well understood. In this pilot study, we evaluate whether CSF NfL and NPTXR are associated with PET-Aß imaging and core CSF biomarkers (Aß42, T-tau, and P-tau). CSF samples were collected from a sub-cohort of participants from the Australian Imaging Biomarkers and Lifestyle study of aging (AIBL) and categorized as either PET-Aß positive (n = 15) or negative (n = 15). NPTXR was significantly lower in PET-Aß positive than negative individuals (p =  0.04), and correlated with Aß42 (rho = 0.69, p <  0.0001), T-tau (rho = 0.45, p =  0.01), and P-tau (rho = 0.51, p =  0.004). However, CSF NfL was not significantly different between PET-Aß positive and negative individuals and did not correlate with any of the core CSF biomarkers. Similar associations of NPTXR and the core CSF biomarkers persisted in the cognitively normal individuals. Together, NPTXR concentration in CSF may be more sensitive NfL to identify AD risk during the preclinical stage, warranting further investigation into its contribution to AD pathogenesis.

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease.

INTRODUCTION: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. METHODS: CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). RESULTS: CSF NfL levels as well as NfL/amyloid ß (Aß42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aß42). CSF NfL and NfL/Aß42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aß42 predicted cortical amyloid load, brain atrophy, and cognition. DISCUSSION: CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.

Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is a multifactorial age-related brain disease. Numerous pathological events run forth in the brain leading to AD. There is an initial long, dormant phase before the clinical symptoms become evident. There is a need to diagnose the disease at the preclinical stage since therapeutic interventions are most likely to be effective if initiated early. Undoubtedly, the core cerebrospinal fluid (CSF) biomarkers have a good diagnostic accuracy and have been used in clinical trials as end point measures. However, looking into the multifactorial nature of AD and the overlapping pathology with other forms of dementia, it is important to integrate the core CSF biomarkers with a broader panel of other biomarkers reflecting different aspects of pathology. The review is focused upon a panel of biomarkers that relate to different aspects of AD pathology, as well as various studies that have evaluated their diagnostic potential. The panel includes markers of neurodegeneration: neurofilament light chain and visinin-like protein (VILIP-1); markers of amyloidogenesis and brain amyloidosis: apolipoproteins; markers of inflammation: YKL-40 and monocyte chemoattractant protein 1; marker of synaptic dysfunction: neurogranin. These markers can highlight on the state and stage-associated changes that occur in AD brain with disease progression. A combination of these biomarkers would not only aid in preclinical diagnosis, but would also help in identifying early brain changes during the onset of disease. Successful treatment strategies can be devised by understanding the contribution of these markers in different aspects of disease pathogenesis.

Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-ß.

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-ß (Aß). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aß burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aß burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aß burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aß burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin.

Neuroserpin is a serine protease inhibitor that regulates the activity of plasmin and its activators in the neuronal tissues. This study provides novel evidence of regulatory effect of the neuroserpin on plasmin proteolytic activity in the retina in glaucoma. Human retinal and vitreous tissues from control and glaucoma subjects as well as retinas from experimental glaucoma rats were analysed to establish changes in plasmin and neuroserpin activity. Neuroserpin undergoes oxidative inactivation in glaucoma which leads to augmentation of plasmin activity. Neuroserpin contains several methionine residues in addition to a conserved reactive site methionine and our study revealed enhanced oxidation of Met residues in the serpin under glaucoma conditions. Met oxidation was associated with loss of neuroserpin inhibitory activity and similar findings were observed in the retinas of superoxide dismutase (SOD) mutant mice that have increased oxidative stress. Treatment of purified neuroserpin with H2O2 further established that Met oxidation inversely correlated with its plasmin inhibitory activity. Dysregulation of the plasmin proteolytic system associated with increased degradation of the extracellular matrix (ECM) proteins in the retina. Collectively, these findings delineate a novel molecular basis of plasmin activation in glaucoma and potentially for other neuronal disorders with implications in disease associated ECM remodelling.

Insulin signaling: An opportunistic target to minify the risk of Alzheimer's disease.

Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism are leading to the Aß (Aß) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Aß transport through central to peripheral and vice versa. Several pathways, like enzymatic degradation of Aß, forkhead box protein O1 (FOXO) signaling, insulin signaling shared common pathological mechanism for both AD and DM. Recent evidence showed that hyperinsulinemia and hyperglycemia affect the onset and progression of AD differently. Some researchers have suggested that hyperglycemia influences vascular tone, while hyperinsulinemia may underlie mitochondrial deficit. The objective of this review is to determine whether existing evidence supports the concept that impairment in insulin signaling and glucose metabolism play an important role in pathogenesis of AD. In the first part of this review, we tried to explain the interconnecting link between AD and DM, whereas the second part includes more information on insulin resistance and its involvement in AD pathogenesis. In the final part of this review, we have focused more toward the AD treatment by targeting insulin signaling like anti-diabetic, antioxidant, nutraceuticals and dietary supplements. To date, more researches should be done in this field in order to explore the pathways in insulin signaling, which might ameliorate the treatment options and reduce the risk of AD due to DM.

Altered levels of blood proteins in Alzheimer's disease longitudinal study: Results from Australian Imaging Biomarkers Lifestyle Study of Ageing cohort.

INTRODUCTION: A blood-based biomarker panel to identify individuals with preclinical Alzheimer's disease (AD) would be an inexpensive and accessible first step for routine testing. METHODS: We analyzed 14 biomarkers that have previously been linked to AD in the Australian Imaging Biomarkers lifestyle longitudinal study of aging cohort. RESULTS: Levels of apolipoprotein J (apoJ) were higher in AD individuals compared with healthy controls at baseline and 18 months (P = .0003) and chemokine-309 (I-309) were increased in AD patients compared to mild cognitive impaired individuals over 36 months (P = .0008). DISCUSSION: These data suggest that apoJ may have potential in the context of use (COU) of AD diagnostics, I-309 may be specifically useful in the COU of identifying individuals at greatest risk for progressing toward AD. This work takes an initial step toward identifying blood biomarkers with potential use in the diagnosis and prognosis of AD and should be validated across other prospective cohorts.

Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging.

INTRODUCTION: For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. METHODS: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini-mental state examination score, plasma amyloid beta (Aß), neocortical Aß burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. RESULTS: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P < .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Aß1-42/Aß1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. DISCUSSION: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms.

Multiplex biomarkers in blood.

Advances in the field of blood biomarker discovery will help in identifying Alzheimer's disease in its preclinical stage, allowing treatment to be initiated before irreversible damage occurs. This review discusses some recent past and current approaches being taken by researchers in the field. Individual blood biomarkers have been unsuccessful in defining the disease pathology, progression and thus diagnosis. This directs to the need for discovering a multiplex panel of blood biomarkers as a promising approach with high sensitivity and specificity for early diagnosis. However, it is a great challenge to standardize a worldwide blood biomarker panel due to the innate differences in the population tested, nature of the samples and methods utilised in different studies across the globe. We highlight several issues that result in the lack of reproducibility in this field of research currently faced by researchers. Several important measures are summarized towards the end of the review that can be taken to minimize the variability among various centres.

TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders.

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches.

Biomarkers of Alzheimer's disease among Mexican Americans.

BACKGROUND: Mexican Americans are the fastest aging segment of the U.S. population, yet little scientific literature exists regarding the Alzheimer's disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American. METHODS: Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer's Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses. RESULTS: The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g., FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.77, 0.92, and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of sensitivity and specificity. CONCLUSION: The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted.

Garlic extract exhibits antiamyloidogenic activity on amyloid-beta fibrillogenesis: relevance to Alzheimer's disease.

Alzheimer's disease is characterized pathologically by the deposition of amyloid plaques. Fibrillar Abeta is the principal component of amyloid plaques in the brain of AD patients. The prevention of Abeta aggregation or dissolution of fibrillar Abeta has clinical significance. The present communication examined in vitro the antiamyloidogenic properties of garlic extract. The effects of aqueous garlic extract (both fresh and boiled) on Abeta aggregation and defibrillation were studied by thioflavin-T based fluorescence assay, transmission electron microscopy and SDS-polyacrylamide gel electrophoresis. The aqueous fresh garlic extract not only inhibited Abeta fibril formation in a concentration and time dependent manner but was also able to defibrillate Abeta preformed fibrils. The maximum defibrillization was observed after 2-3 days of incubation. The boiled aqueous garlic extract also retained its antiamyloidogenic activity. This indicated that antiamyloidogenic activity of garlic extract is non-enzymatic, i.e. proteases present in garlic did not degrade Abeta in solution. However, the fibril degrading ability of boiled garlic extract was significantly lost. The findings suggest that consumption of garlic may lead to inhibition of Abeta aggregation in human brain.

Studies on the role of amino acid stereospecificity in amyloid beta aggregation.

Amyloid beta (Abeta) deposition and neurodegeneration are the two related events in the pathogenesis of Alzheimer's disease. Several factors modulate the conformation and physical properties of Abeta, which in turn affects its biological functions. Among these, age-dependent changes in the stereospecificity of the amino acids comprising Abeta is one such factors. In the present study, we investigated the aggregation property of Abeta as a function of the stereospecificity of amino acids comprising the peptide. We carried out our study by comparing the physical properties of Abeta(1-40) all-L and Abeta(1-40) all-D enantiomers using various biophysical techniques. These results indicated that the aggregation and folding parameters of Abeta are stereospecific and the aggregation property strongly depends upon the amino acid sequence and their stereospecificity. This may possibly help to understand the stereospecific role of amino acids comprising Abeta in its aggregation and its relevance to neurodegeneration.

Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer's beta-amyloid fibrils in vitro.

Alzheimer's disease involves Abeta accumulation, oxidative damage and inflammation and there is currently no clinically accepted treatment to stop its progression. Its risk is known to reduce with increased consumption of antioxidant and anti-inflammatory agents. Fibrillar aggregates of Abeta are major constituents of the senile plaques found in the brains of AD patients and have been related to AD neurotoxicity. It is reported that SAC (S-allyl-l-cysteine), a water-soluble organosulfur component present in garlic is known to prevent cognitive decline by protecting neurons from Abeta induced neuronal apoptosis. Hence, we investigated the effects of SAC on Abeta aggregation by employing Thioflavin-T, transmission electron microscopy, SDS-PAGE, size exclusion-HPLC. Under aggregating conditions in vitro, SAC dose-dependently inhibited Abeta fibrillation and also destabilized preformed Abeta fibrils. Further, Circular dichroism and fluorescence quenching studies supported the binding ability of SAC to Abeta and inducing a partially folded conformation in Abeta. The 3D structure of Abeta-SAC complex was also predicted employing automated docking studies.