Presence Of Β-amyloid Research Articles

Amyloid beta-activated alpha-1-syntrophin has ramifications on Rac1 activation, ROS production and neuronal cell death.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of β-amyloid (Aβ)-containing extracellular neuritic plaques and phosphorylated tau-containing intracellular neurofibrillary tangles. It remains the primary neuropathological criteria for the diagnosis of AD. Additionally, several other processes are currently being recognized as significant risk factors for AD development, including the brain's susceptibility to reactive oxygen species (ROS). The ROS production is among the early signs in the progression of AD. However, the underlying mechanisms behind increased ROS production in AD remain poorly understood. We have observed SNTA1 plays critical role in regulating ROS levels in different pathological conditions. Here, we wanted to gain further insight into the role of SNTA1 in the development of AD by using IMR32 cell line. Our results show that the accumulation of Aβ plaques in Alzheimer's model neuroblastoma cells significantly increases the expression and activation of SNTA1 and MKK6 kinase. The activation of MKK6 results in the phosphorylation of SNTA1, creating a binding site for Rac1, leading to its activation and subsequent production of ROS. Excessive ROS production leads to cell cycle arrest in the G2/M phase, a hallmark of AD. Our study provides new insight into the mechanism of Aβ-mediated cell death in AD and suggests that MKK6-mediated activation of alpha-1-syntrophin promotes ROS production in neuronal cells, resulting in cell death. This study presents a mechanistic insight into Aβ-mediated cell death and could serve as a paradigm for reducing neuronal cell death in AD.

A Comprehensive Review on Alzheimer’s Disease its Pathogenesis, Epidermiology, Diagnostics and Treatment

The global impact of Alzheimer's disease (AD) is significant. The current prevalence of Major Neurocognitive Disorder is estimated to affect approximately 44 million individuals. Presently, the United States harbors a population of approximately 6.2 million individuals who are afflicted by Alzheimer's disease (AD) dementia. It is of significance to highlight that mortality associated with Alzheimer's disease (AD) exceeds the combined mortality rates of both breast cancer and prostate cancer. Based on the findings of the National Institute on Aging, the frequency of Alzheimer's disease (AD) exhibits a twofold rise every five years subsequent to attaining the age of 65. Furthermore, with the ongoing process of population aging, an increasingly substantial portion of the population is affected by this particular condition. Based on forecasts, it is anticipated that the United States will experience a financial impact of $355 billion in 2021 as a result of Alzheimer's disease (AD).
 Furthermore, same projections indicate that this amount is expected to increase significantly to over $1.5 trillion by the year 2050. As a result, this would place a significant financial strain on the country. Alzheimer's disease (AD) is a neurodegenerative condition that is distinguished by the existence of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles consisting of hyperphosphorylated τ-protein. The aforementioned abnormal characteristics primarily present themselves inside the cortical and limbic regions of the human brain. The aforementioned ailment is characterized by the presence of memory impairment and a progressive deterioration of neurocognitive abilities. The atypical division of amyloid precursor protein (APP) by β-secretases and γ-secretases leads to the production of Aβ40 and Aβ42 individual molecules, which then undergo the process of oligomerization and aggregation, finally culminating in the formation of senile plaques. The aforementioned disease is additionally aggravated by pathogenic microorganisms, including the human immunodeficiency virus (HIV).
 Moreover, within the framework of disease pathophysiology, the presence of heightened amounts of Aβ peptides within the central nervous system induces the infiltration of microglial cells. Presently, there exists a notable focus within the realm of scientific inquiry on gaining a comprehensive understanding of the pathological nature of Alzheimer's disease (AD) by means of exploring diverse pathways.
 These mechanisms include the abnormal metabolism of tau proteins, the presence of β-amyloid, the inflammatory response, as well as the damage caused by cholinergic dysfunction and free radicals. The ultimate objective of this research is to develop efficacious treatments that can effectively halt or alter the progression of AD. The present study provides an analysis of the pathophysiological mechanisms underlying Alzheimer's disease, as well as an examination of the diagnostic methods employed in its identification. Furthermore, the review explores the many therapy modalities now utilized in managing this neurodegenerative disorder.

Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer's Disease via Gut Microbiome.

Alzheimer's disease (AD) is a chronic neurodegenerative disease, characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau proteins (ptau). To date, there is no cure for AD. Earlier therapeutic efforts have focused on the clinical stages of AD. Despite paramount efforts and costs, pharmaceutical interventions including antibody therapies targeting Aβ have largely failed. This highlights the need to alternate treatment strategies and a shift of focus to early pre-clinical stages. Approximately 25-40% of AD cases can be attributed to environmental factors including chronic stress. Gut dysbiosis has been associated with stress and the pathogenesis of AD and can increase both Aβ and NFTs in animal models of the disease. Both stress and enrichment have been shown to alter AD progression and gut health. Targeting stress-induced gut dysbiosis through probiotic supplementation could provide a promising intervention to delay disease progression. In this review, we discuss the effects of stress, enrichment, and gut dysbiosis in AD models and the promising evidence from probiotic intervention studies.

Assessment of tau phosphorylation and β-amyloid pathology in human drug-resistant epilepsy.

Epilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy. Cortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ). We found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong. These findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.

Interaction between Alzheimer's Disease and Cerebral Small Vessel Disease: A Review Focused on Neuroimaging Markers.

Alzheimer’s disease (AD) is characterized by the presence of β-amyloid (Aβ) and tau, and subcortical vascular cognitive impairment (SVCI) is characterized by cerebral small vessel disease (CSVD). They are the most common causes of cognitive impairment in the elderly population. Concurrent CSVD burden is more commonly observed in AD-type dementia than in other neurodegenerative diseases. Recent developments in Aβ and tau positron emission tomography (PET) have enabled the investigation of the relationship between AD biomarkers and CSVD in vivo. In this review, we focus on the interaction between AD and CSVD markers and the clinical effects of these two markers based on molecular imaging studies. First, we cover the frequency of AD imaging markers, including Aβ and tau, in patients with SVCI. Second, we discuss the relationship between AD and CSVD markers and the potential distinct pathobiology of AD markers in SVCI compared to AD-type dementia. Next, we discuss the clinical effects of AD and CSVD markers in SVCI, and hemorrhagic markers in cerebral amyloid angiopathy. Finally, this review provides both the current challenges and future perspectives for SVCI.

A Review on: Alzheimer’s disease and mechanistic insights of bioactive compounds in its treatment

Alzheimer’s disease is a most common neurological disorder, associated with cognitive disorder. Pathologically, Alzheimer's disease is characterized via the presence of β-amyloid (Aβ) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, but persistence oxidative-nitrative stress, endoplasmic reticulum pressure, mitochondrial disorder, inflammatory cytokines, pro-apoptotic proteins in conjunction with altered neurotransmitters degree are common etiological attributes in its pathogenesis. With the modern state of affairs, the variety of published proofs shows the neuroprotective capability of evidently occurring bioactive molecule via their anti-oxidant, ant apoptotic and neutransmitter modulatory residences. Many researchers have counselled that change of life style, proper diet, can delay or prevent the onset of this ailment. Diet is presently considered to be an important component in controlling fitness and protecting oneself towards oxidative strain and persistent inflammation, and hence towards chronic degenerative illnesses. A wide variety of bioactive food compounds may impact the pathological mechanisms underlying AD. Among them, phenolic compounds, omega-three fatty acids, fats-soluble vitamins, isothiocyanates, seem like the best in stopping neurodegeneration. The present review gathers proof that helps the neuroprotective impact of bioactive materials. Keywords: Alzheimer’s disease, neurodegeneration, amyloid cascade, tau protein, tau hypothesis, nitric oxide

Synthesis and approbation of new neuroprotective chemicals of pyrrolyl- and indolylazine classes in a cell model of Alzheimer's disease.

One of the major causes of neurodegeneration in the pathogenesis of Alzheimer's disease is the accumulation of cytotoxic amyloid species within the intercellular compartments of the brain. The efficacy of the anti-proteotoxic mechanism based on the molecular chaperones Hsp70 and Hsp90 in numerous types of neurons is often low, while its pharmacological enhancement has been shown to ameliorate the physiological and cognitive functions of the brain. Suggesting that the chemicals able to induce heat shock protein synthesis and therefore rescue neural cells from cytotoxicity associated with amyloid, we have synthesized a group of pyrrolyl- and indolylazines that cause the accumulation of heat shock proteins, using a novel method of photocatalysis that is employed in green chemistry. The selected compounds were tested in a cell model of Alzheimer's disease and demonstrated a pronounced neuroprotective effect. These substances increased the survival of neurons, blocked the activation of β-galactosidase, and prevented apoptosis in neurons cultured in the presence of β-amyloid.

Nutraceuticals and their Derived Nano-Formulations for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. The presence of β-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmarks of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence showed the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceuticals suffer from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic- metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to overcome such issues, various nanoformulations of nutraceuticals have been developed, that allow their effective delivery into the brain owing to reduced particle size, increased lipophilicity, increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focusing on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitations and regulatory aspects of nutraceuticals to ensure safety and efficacy. We have further explored various nanoformulations of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitations and for effective delivery into the brain.

Mitochondrial dysfunction, mitophagy, and role of dynamin-related protein 1 in Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and progressive neurodegenerative disease. The presence of β-amyloid (Aβ) plaques and phosphorylated Tau tangles are considered to be the two main hallmarks of AD. Recent findings have shown that different changes in the structure and dynamics of mitochondria play an important role in AD pathology progression. Mitochondrial changes in AD are expressed as enhanced mitochondrial fragmentation, altered mitochondrial dynamics, and changes in the expression of mitochondrial biogenesis genes in vitro and in vivo models. Therefore, targeting mitochondria and associated mitochondrial proteins seems to be a promising alternative instead of targeting Aβ and Tau in the prevention of Alzheimer's disease. The dynamin-related protein (Drp1) is one such protein that plays an important role in the regulation of mitochondrial division and maintenance of mitochondrial structures. Few researchers have shown that inhibition of Drp1 GTPase activity in neuronal cells rescues excessive mitochondrial fragmentation. In addition, the growing evidence revealed that Drp1 can interact with both Aβ and Tau protein in human brain tissues and mouse models. In this review, we would like to update existing knowledge about various changes in and around mitochondria related to the pathogenesis of Alzheimer's disease, with particular emphasis on mitophagy and autophagy.

A β-Amyloid(1-42) Biosensor Based on Molecularly Imprinted Poly-Pyrrole for Early Diagnosis of Alzheimer's Disease.

Background: Alzheimer’s disease (AD) is a common form of dementia, characterized by production and deposition of β-amyloid peptide in the brain. Thus, β-amyloid peptide is a potentially promising biomarker used to diagnose and monitor the progression of AD. Objective: The study aims to develop a biosensor based on a molecularly imprinted poly-pyrrole for detection of β-amyloid.Material and Methods: In this experimental study, an imprinted poly-pyrrole was employed as an artificial receptor synthesized by electro-polymerization of pyrrole on screen-printed carbon electrodes in the presence of β-amyloid. β-amyloid acts as a molecular template within the polymer. The biosensor was evaluated by cyclic voltammetry using ferro/ferricyanide marker. The parameters influencing the biosensor performance, including electro-polymerization cycle umbers and β-amyloid binding time were optimized to achieve the best biosensor sensitivity. Results: The β-amyloid binding affinity with the biosensor surface was evaluated by the Freundlich isotherm, and Freundlich constant and exponent were obtained as 0.22 ng mL-1 and 10.60, respectively. The biosensor demonstrated a detection limit of 1.2 pg mL-1. The biosensor was applied for β-amyloid determination in artificial cerebrospinal fluid. Conclusion: The biosensor is applicable for early Alzheimer’s disease detection.

Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer’s disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer’s Association (NIA-AA) A/T/(N) [β-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [β-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of β-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as “mismatch MCI” for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because β-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or “prodromal AD”) and A-T-(N+) MCI (or “neurodegeneration-only MCI”) on cross-sectional and longitudinal cognition and neuroimaging characteristics. β-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less “AD-like” than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that β-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.

Current Quest in Natural Bioactive Compounds for Alzheimer's Disease: Multi-Targeted-Designed-Ligand Based Approach with Preclinical and Clinical Based Evidence.

Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of β-amyloid (Aβ) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/β secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults.

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18F-flortaucipir (FTP) and 11C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aβ, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages.SIGNIFICANCE STATEMENT Tau and β-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aβ may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aβ, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aβ+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

Neuroprotection of SAK3 on scopolamine-induced cholinergic dysfunction in human neuroblastoma SH-SY5Y cells.

Alzheimer's disease (AD) is the most common type of senile dementia. A number of factors have been proposed regarding pathology of AD, such as presence of β-amyloid, and cholinergic and oxidative stress. SAK3 (ethyl 8'-methyl-2',5-dioxo-2-piperidin-1-ylspiro[cyclopentene-3,3'-imidazo[1,2-a]pyridine]-1-carboxylate) reduces β-amyloid deposition and improves cognitive functions in amyloid precursor protein knock-in mice. Scopolamine is used to induce in cell lines a cholinergic deficit that mimics AD. In order to evaluate the possible neuroprotective properties of SAK3, human neuroblastoma SH-SY5Y cells were pretreated with the compound (25-100nM) and further incubated in the presence of scopolamine (2mM). SAK3 inhibited scopolamine-induced cellular apoptosis (morphologically and by determination of pro- and anti-apoptotic factor levels), increase in ROS levels, decrease in choline acetyltransferase level, phosphorylation of NF-κB, activation of Akt, JNK and p38 intracellular signaling pathways, and elevation of proinflammatory cytokines IL-1β and IL-6, but not enhanced level of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). These results indicate SAK3 possessed protective properties against cholinergic deficit associated with anti-oxidant, anti-apoptotic and anti-inflammatory activities, suggesting that SAK3 might be a potential agent in the development of AD drug therapeutics.

Orientin Improves Cognition by Enhancing Autophagosome Clearance in an Alzheimer's Mouse Model.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the presence of β-amyloid (Aβ) plaques and defective autophagy in the brain, which is believed to cause neuronal dysfunction. By using APP/PS1 transgenic AD mice, we investigated the influence of orientin (Ori) on cognitive function and its underlying mechanisms in AD models. Our data indicated that Ori improved spatial learning and memory in APP/PS1 mice, possibly through decreasing brain Aβ deposition and attenuating autophagy impairment. Ori decreased the LC3-II/I ratio, p62 and cathepsin D (Ctsd) protein levels and the number of autolysosomes, whereas the protein levels of Ulk1 and Beclin-1 were no different between the control and treatment groups, indicating increased autolysosome clearance and thus a decreased Aβ burden in the brain. Our results showed that Ori could enhance autolysosome clearance, decrease brain Aβ deposition and improve learning and memory in AD mice.

V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function

The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 could be regulating multiple cellular compartments. Here, we investigated the function of wild-type human PLD3 (PLD3WT) and the Val232Met variant (PLD3VM) in the presence of β-amyloid (Aβ) in a Drosophila melanogaster model of AD. We expressed PLD3WT in CNS of the Aβ-model flies and monitored its effect on the ER stress, cell apoptosis and recovery the Aβ-induced cognitive impairment. The expression reduced ER stress and neuronal apoptosis, which resulted in normalized antioxidative phospholipids levels and brain protection. A specific O-glycosylation at pT271 in PLD3 is essential for its normal trafficking and cellular localization. The V232 M substitution impairs this O-glycosylation, leading to enlarged lysosomes and plausibly aberrant protein recycling. PLD3VM was less neuroprotective, and while, PLD3WT expression enhances the lysosomal functions, V232 M attenuated PLD3's trafficking to the lysosomes. Thus, the V232 M mutation may affect AD pathogenesis. Further understanding of the mechanistic role of PLD3 in AD could lead to developing novel therapeutic agents.

The influence of β-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia.

To compare [18F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ). Thirty-one participants with svPPA underwent MRI and Pittsburgh compound B-PET scanning, and 17 of these also underwent [18F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [18F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(-) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(-) controls. Of the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(-) participants. svPPA showed elevated [18F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia. Although [18F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [18F]AV-1451 in svPPA is related to binding paired helical filament tau.

A New Iq-Peptide of the Kunitz Type from the Heteractis magnifica Sea Anemone Exhibits Neuroprotective Activity in a Model of Alzheimer’s Disease

The HMIQ3c1 recombinant peptide (6434 Da), the Kunitz-type protease inhibitor, which belonged to the new group of the IQ-peptides from the Heteractis magnifica sea anemone was prepared. The inhibitory constant of trypsin by this peptide proved to be 5.0 × 10–8 M. rHMIQ3c1 was shown to have no interaction with eight isoforms of Kv1 channels. This peptide exhibited neuroprotective activity in a concentration of 10 μM, and the peptide increased the viability of cells of the Neuro2a murine neuroblastoma by 39.4 ± 6.6% in the presence of β-amyloid. However, the peptide did not influence the viability of the cells during their incubation with 6-hydroxydofamine.

Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later.

ObjectiveTo evaluate the effect of midlife lipid levels on Alzheimer brain pathology 20 years later in cognitively normal elderly individuals.MethodsThis is a longitudinal cohort study of 318 cognitively normal individuals with data on fasting lipid levels at midlife (mean age 54 years). Presence of β-amyloid (Aβ) and tau pathologies 20 years later (mean age 73 years) were detected by quantifying Alzheimer disease (AD) biomarkers in CSF. In a subset (n = 134), Aβ (18F-flutemetamol) PET was also performed.ResultsCSF Aβ42 and Aβ PET revealed Aβ pathology in approximately 20% of the cognitively healthy population and CSF Aβ42/phosphorylated tau (p-tau) ratio indicated both Aβ and tau pathology in 16%. Higher levels of triglycerides in midlife were independently associated with abnormal CSF Aβ42 (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.03–1.75, p = 0.029) and abnormal Aβ42/p-tau ratio (OR 1.46, 95% CI 1.10–1.93; p = 0.009) adjusting for age, sex, APOE ε4, education, and multiple vascular risk factors. Triglycerides were also associated with abnormal Aβ PET in multivariable regression models, but the association was attenuated in the fully adjusted model. Increased levels of medium and large low-density lipoprotein subfractions were significantly associated with abnormal Aβ PET and large high-density lipoprotein particles were associated with decreased risk of abnormal Aβ PET.ConclusionsIncreased levels of triglycerides at midlife predict brain Aβ and tau pathology 20 years later in cognitively healthy individuals. Certain lipoprotein subfractions may also be risk factors for Aβ pathology. These findings further support an involvement of lipids in the very early stages of AD development.

Regional patterns of gray matter volume, hypometabolism, and beta-amyloid in groups at risk of Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence of β-amyloid (Aβ) deposition and neurodegeneration. To seek for signs of such pathologies, we compared regional biomarker degrees and patterns of Aβ deposition, glucose hypometabolism, and gray matter volume (GMV) reduction in 3 groups at risk of AD. In elderly carriers of the apolipoprotein E ε4 (APOE4, n = 17), patients with subjective cognitive decline (n = 16), and patients with mild cognitive impairment (n = 30), head-to-head intermodality comparisons were performed on cross-sectional structural magnetic resonance images as well as 18F-fluorodeoxyglucose and 18F-florbetapir positron emission tomography scans. In mild cognitive impairment patients, 3 distinct biomarker patterns were recovered, similarly seen in AD patients: (1) in medial temporal regions, local GMV reduction exceeded hypometabolism, (2) in temporoparietal regions, hypometabolism predominated over GMV reduction, and (3) in frontal regions, Aβ deposition exceeded GMV reduction and hypometabolism. In subjective cognitive decline patients, only pattern 1 was detected, while APOE4 carriers demonstrated only pattern 3. Our findings highlight that regional AD-like biomarker patterns may vary across different at-risk populations, potentially reflecting differential mediators of these risks.