Presence Of Aβ Plaques Research Articles

Early PSA-NCAM reduction in the dentate gyrus and impaired plasticity in the Alzheimer´s disease 3xTg-mice model

Neurodegenerative diseases such as Alzheimer´s (AD) and physiological ageing are characterized by a decline in neurogenesis and in the polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and specifically in the dentate gyrus (DG). In the 3xTG-AD mouse model, which mimics the human disease in both pathological and behavioral features, this decline in PSA-NCAM is associated with the presence of Aβ plaques at 9 months and Tau tangles at 12–15 months. In this work we studied the presence of PSA-NCAM at early ages (1–6 months) in the same model. Our results demonstrated that even as early as the first month of age there is a strong decrease in PSA-NCAM dendritic tree mainly altering the molecular layer (MolL) coverage affecting the synaptic plasticity and furthermore confirmed by the reduction of PSA-NCAM area density (Sv) in the 3xTG-AD. Similar and more marked early changes were seen during aging in both NTG and 3xTg-AD animals. Our results demonstrate for the first time a precipitate decrease of PSA-NCAM cells at such very early phases of the disease. This result suggests an early effect of the disease in the progression of immature and pluripotent cells resulting in an ulterior and early diminution of neurogenesis and therefore an impaired hippocampal cellular and synaptic plasticity.

An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

Metabolic effect of the retina in a murine model of AD

Aims/Purpose: The aim of the study is to evaluate energy metabolism and retinal tissue survival in retinal explants in a murine model of AD (TgSwDI) during aging.Methods: The 7‐, 12‐ and 24‐month‐old TgSwDI mouse model was compared with age‐matched wild‐type (WT) mice. Characterization of the mouse model was assessed by Aβ plaques staining. Cell viability was evaluated by lactate dehydrogenase (LDH) assay of retinal explants at 4 and 24 h of incubation with culture media. Retinal ganglion cell (RGC) survival was quantified by RBPMS staining in 7‐month‐old mice. Glucose metabolism was analysed by gas chromatography mass spectrometry (GC–MS) using uniformly labelled glucose by incubating whole retinas for 30 min with glucose in 7‐month‐old mice. And lactate, produced by glycolysis, was evaluated by the lactate assay in 7‐month‐old mice.Results: The presence of Aβ plaques and vascularization was detected in the retinas of TgSwDI mice, whereas they were not found in the retinas of control mice. At 7 months, the viability of retinal explants was reduced in the TgSwDI model compared to the age‐matched WT model using the LDH assay. Compared to controls, RGC survival in the TgSwDI model tended to decrease. We performed GC–MS to evaluate glucose metabolism and observed no difference between the TgSwDI and WT groups. Lactate production showed no significant differences between the groups.Conclusions: The presence of Aβ plaques was detected in the retinas of the TgSwDI model, indicating that it is a good model for studying the retina in AD. Retinal tissue viability was altered at different ages in the TgSwDI model, and RGC survival was also reduced in the AD model, substantiating that AD affect the retina. We did not detect any differences between WT and TgSwDI groups in energy metabolism, implying that alterations in retinal tissue and cell survival may be related to other pathways. Further studies are needed to explore this, ultimately providing novel insight to address visual function affected by AD.

40 Hz Electroacupuncture relieves the memory dysfunction of 5xFAD mice by regulating neuronal electrical activity

In this investigation, we probed the impacts of 40 Hz Electroacupuncture (EA) on the cognitive function and brain activity in 5xFAD mice. Three groups of mice were constituted: the Model group of 5xFAD mice, the Wild Type (WT) group of littermate controls, and the EA group of 5xFAD mice subjected to EA treatment. Behavioral tests were conducted to evaluate memory function and anxiety levels, while the presence of Aβ plaques were detected via immunostaining, and neuronal activity was measured using multichannel recordings. Our results indicated that EA therapy enhanced memory function and anxiety-like behavior in 5xFAD mice, as well as diminishing the abundance and dimensions of Aβ plaques in the hippocampus and mPFC regions. Notably, the suppression of astrocyte activation was observed, which was potentially associated with alterations in gamma oscillation. Furthermore, the synaptic transmission of neurons was amplified, suggesting a possible modulation in neural activity. These findings indicate that 40 Hz EA could influence cognitive performance and potentially affect neuronal activity in 5xFAD mice, while the direct connection between EA and neuronal electrical activity regulation requires further exploration. The potential frequency-specific effects of EA on protective mechanisms in the brain was not addressed in this study and thus presents a direction for future research.

Morphofunctional Investigation in a Transgenic Mouse Model of Alzheimer's Disease: Non-Reactive Astrocytes Are Involved in Aβ Load and Reactive Astrocytes in Plaque Build-Up.

The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM), and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β (Aβ) peptide is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed to investigate the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time-persistent disassembly of functional astroglial syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of the disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Brain region-specific myelinogenesis is not directly linked to amyloid-β in APP/PS1 transgenic mice

Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (Aβ). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether Aβ, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and Aβ deposits displayed a region-specific pattern in the 13-month-old APP/PS1 transgenic mouse brains. Aβ plaques cause focal demyelination, but only about 15% Aβ plaques are closely associated with newly formed myelin in the APP/PS1 brains. Further, the Aβ plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that Aβ plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble Aβ in regulating myelinogenesis, we chose to observe the visual system, wherein soluble Aβ is detectable but without the presence of Aβ plaques in the APP/PS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APP/PS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble Aβ probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble Aβ (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFRα positive OPCs in vitro. Consistently, injection of soluble Aβ into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt; Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to Aβ, but rather probably a synergic result in adapting to AD pathology.

Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by substantial neuronal damage which manifests in the form of deficits in memory and cognition. In spite of the debilitating nature of Alzheimer's disease (AD), a dearth of treatment strategies calls for the need to develop therapeutic agents that stimulate neurogenesis and alleviate the associated cognitive deficits. The present study investigates the therapeutic potential of two major phytochemicals, rosmarinic acid (RA) and ursolic acid (UA) in an amyloid beta1-42 (Aβ1-42)-induced model of AD. UA, a natural pentacyclic triterpenoid and RA, a phenolic ester are major bioactive constituents of Rosmarinus officinalis, which is a medicinal herb belonging to family Lamiaceae and exhibiting significant biological properties including neuroprotection. Donepezil, a second generation cholinesterase inhibitor approved for the treatment of mild, moderate and severe Alzheimer's disease (AD) is used as control. Out of eight groups of male BALB/c mice, stereotaxic surgery was performed on four groups (n = 6 each) to introduce Aβ1-42 in the hippocampus followed by treatment with vehicle (phosphate-buffered saline (PBS)), donepezil, UA or RA. The other four groups were given vehicle, donepezil, UA and RA only. Behavior analysis for social interaction was performed which constitutes the social affiliation and the social novelty preference test. Presence of Aβ plaques and expression of neurogenesis markers i.e., doublecortin (DCX) and Ki-67 were also assessed. Results revealed the neuroprotective effect of UA and RA observed through substantial reduction in Aβ plaques as compared to the Aβ1-42- and donepezil-treated groups. The neuronal density was also restored as evident via DCX and Ki-67 immunoreactivity in Aβ1-42 + RA and Aβ1-42+UA-treated groups in comparison to Aβ1-42-treated and Aβ1-42+donepezil-treated groups. The social affiliation was reestablished in the Aβ1-42 administered groups treated with UA and RA. Molecular docking studies further validated the comparable binding of UA and RA with Ki-67 and DCX to that of donepezil. Our findings suggest that UA and RA are potential neuroprotective compounds that reverses the histological hallmarks of AD and ameliorate impaired social memory and hippocampal neurogenesis.

Value of the retina in the diagnosis of Alzheimer's disease

AbstractVision, which is a process that requires the involvement of a large number of neurons, is often impaired during Alzheimer's disease (AD). Over the past few decades, research has shown that several visual functions and structures are compromised during AD and can also be used to differentiate affected individuals from those who show normal aging. Retina is a projection from the central nervous system and shares many features with the brain. Classically, the damage in AD was thought to be restricted mainly to the brain. However, in the last years it has been demonstrated in retinas of AD human postmortem specimens, the presence of Aβ plaques and pTau deposition, being more abundant in the superior region of the retina matching with greater neuronal degeneration. Also, it has been suggested that Aβ plaques in the retina may anticipate those in the brain. In addition, recently it has also been possible to observe in vivo Aβ plaques in human retinas, with imaging techniques and ingesting curcumin as a marker of Aβ deposits. Recently, using in vivo hyperspectral imaging techniques in the retina, it has been reported that Aβ load in the brain can be predicted. These findings provide histopathological evidence that the visual system may be altered much earlier in the AD disease process than previously thought, and thus support the use of visual biomarkers in the early detection of the disease. Current in vivo imaging techniques such as OCT are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of AD patients. In early AD, OCT has demonstrated a thickening of the macular region and a subsequent thinning of the peripapillary area of the retina in more advanced stages of the disease. New analytic methods have shown in AD patients that thinned regions are interspersed with thickened ones in all retinal layers, except inner nuclear and outer segments. This causes roughness to appear on retinal layer thickness maps, finding that Fractal Dimension (FD) of retinal layers is greater in the AD patients, being roughness of retinal layers, assessed by the FD of their thickness maps, a possible early retinal biomarker of AD.In the other hand, recent data suggest the vascular involvement of the retina in AD patients. Vascular changes in the retina are thought to share similar pathogenic mechanisms with cerebral vasculature. OCT and OCT angiography (OCTA) has demonstrated a thinning of the choroidal thickness in early AD and decrease of the foveal avascular zone in patients with moderate AD.All these observations support the value of the retina as a biomarker of AD that will allow us, with the development of new research, to discover new retinal biomarkers that will help us to improve the diagnosis and follow‐up of this growing pathology.

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis.

Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease

The presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (Kd = 8.5 nM) with a phenyl-pyridine ring showed a 98-fold increase in fluorescence intensity upon binding with Aβ aggregates. In addition, 4b could identify Aβ plaques in brain sections of both a transgenic (Tg) mouse and AD patients. Furthermore, 4b could readily penetrate the mouse blood-brain barrier (brain2min = 10.11% ID/g) and washed out rapidly. Finally, the NIR imaging with Tg mice confirmed the practical application of 4b in detecting Aβ plaques in vivo. Altogether, our work widens the landscape of Aβ NIR probes and offers a new tool for Aβ detection.

The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer's Disease Pathogenesis.

Alzheimer’s disease (AD), the most common form of dementia in elderly individuals, is marked by progressive neuron loss. Despite more than 100 years of research on AD, there is still no treatment to cure or prevent the disease. High levels of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain are neuropathological hallmarks of AD. However, based on postmortem analyses, up to 44% of individuals have been shown to have high Aβ deposits with no clinical signs, due to having a “cognitive reserve”. The biochemical mechanism explaining the prevention of cognitive impairment in the presence of Aβ plaques is still unknown. It seems that in addition to protein aggregation, neuroinflammatory changes associated with aging are present in AD brains that are correlated with a higher level of brain iron and oxidative stress. It has been shown that iron accumulates around amyloid plaques in AD mouse models and postmortem brain tissues of AD patients. Iron is required for essential brain functions, including oxidative metabolism, myelination, and neurotransmitter synthesis. However, an imbalance in brain iron homeostasis caused by aging underlies many neurodegenerative diseases. It has been proposed that high iron levels trigger an avalanche of events that push the progress of the disease, accelerating cognitive decline. Patients with increased amyloid plaques and iron are highly likely to develop dementia. Our observations indicate that the butyrylcholinesterase (BChE) level seems to be iron-dependent, and reports show that BChE produced by reactive astrocytes can make cognitive functions worse by accelerating the decay of acetylcholine in aging brains. Why, even when there is a genetic risk, do symptoms of the disease appear after many years? Here, we discuss the relationship between genetic factors, age-dependent iron tissue accumulation, and inflammation, focusing on AD.

Alzheimer Disease Pathogenesis: The Role of Autoimmunity.

In addition to deposits of amyloid β (Aβ) plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. The recent failures of clinical trials based on the amyloid hypothesis and the presence of Aβ plaques in cognitively healthy elderly persons without AD point toward a need to explore novel pathobiological mechanisms of AD. In the search for alternative AD mechanisms, numerous genome-wide association studies and mechanistic discoveries suggest a potential immunologic component of the disease. However, new experimental tools are needed to uncover these immunogenic components. The current methods, such as ELISAs or protein microarrays, have limitations of low throughput and/or sensitivity and specificity. In this article, we briefly discuss evidence of potential autoimmune contributions to AD pathobiology, describe the current methods for identifying autoantibodies in patient fluids, and outline our own efforts to develop new techniques for novel autoantibody biomarker discovery. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy. In addition to deposits of amyloid β plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. Numerous research directions, including genome-wide association, clinical correlation, and mechanistic studies, have pointed to a potential autoimmunologic contribution to AD pathology. We present research suggesting the association between autoimmunity and AD and demonstrate the need for new laboratory techniques to further characterize potential brain antigen-specific autoantibodies. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy.

Optimization of solid-phase extraction (SPE) in the preparation of [18F]D3FSP: A new PET imaging agent for mapping Aβ plaques

IntroductionAlzheimer's disease is a common neurodegenerative disease that is characterized by the presence of Aβ plaques in the brain. The FDA has approved the use of Amyvid (florbetapir f18, AV-45) as a PET imaging agent for detecting Aβ plaques in the living human brain. In an attempt to reduce N-demethylation in vivo by taking advantage of more stable C-D bonds, an analog of AV-45, [18F]D3FSP ([18F]7), was synthesized to improve image contrast for detecting and monitoring the Aβ plaques. A convenient and improved preparation of [18F]D3FSP ([18F]7) is needed for widespread clinical application. We report herein the optimization of the radiosynthesis and solid-phase extraction (SPE) procedure. MethodsRadiosyntheses of [18F]D3FSP ([18F]7) under different fluorination conditions were evaluated, and the intermediate, containing an N-Boc protecting group, was deprotected using different acids. One of the major objectives was to simplify the final purification step via SPE to avoid the commonly employed HPLC purification and maximize the radiochemical yields of [18F]D3FSP ([18F]7) while simultaneously removing several chemical impurities (pseudocarriers). Washing various solid-phase cartridges with different combinations of ethanol/water and acetonitrile/water was explored to optimize the purification step. To evaluate the potential interference in Aβ plaques imaging from the presence of pseudocarriers, each chemical was identified and quantified by LC/MS and HPLC. An in vitro binding assay was employed to evaluate the binding affinities of [18F]D3FSP ([18F]7) and the pseudocarriers to Aβ plaques using postmortem AD brain tissue. ResultsUsing the optimized radiosynthesis method and SPE purification, the final dose of [18F]D3FSP ([18F]7) was obtained in 50 min with a very low content of pseudocarriers (21.7 ± 5.5 μg). The radiochemical yield was 44.4 ± 5.7% (decay corrected), and the radiochemical purity was >95%. SPE-purified doses of [18F]D3FSP ([18F]7) displayed excellent binding affinity and specificity for Aβ plaques as measured in an in vitro binding assay using AD brain homogenates, and the OH-pseudocarrier, 8 (Ki = 19.5 ± 0.5 nM), and the Cl-pseudocarrier, 10 (Ki = 18.6 ± 3.9 nM), showed lower binding affinities for Aβ plaques than those of AV-45 (Ki = 8.6 ± 0.5 nM) and D3FSP, 7 (Ki = 9.8 ± 0.5 nM). ConclusionsAn optimized radiosynthesis and fast SPE purification method suitable for the preparation of clinical doses of [18F]D3FSP ([18F]7) was accomplished. The results of quality control tests and binding studies suggested that the SPE-purified doses of [18F]D3FSP ([18F]7) are appropriate for imaging Aβ plaques in the human brain.

Unveiling Amyloid-β1–42 Interaction with Zinc in Water and Mixed Hexafluoroisopropanol Solution in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder caused by overproduction and accumulation of amyloid beta-peptide (Aβ). The hallmarks associated with this AD are the presence of Aβ plaques between the nerve cell in the brain which leading to synaptic loss in memory. The amyloid plaques contain of transition metals like zinc, copper and iron. In a healthy brain, the metal ions are present in balance concentration. High concentrations of Zn are normally released during neurotransmission process. The release of Zn might cause the aggregation of Aβ leading to AD. Amyloid-β1–42 is the main type of Aβ in amyloid plaque. There still have limited explanation on how Aβ1–42 interaction with Zn metal, as well as the effect of Zn metal on the Aβ structure in different solvents in atomic detail. Therefore, we investigated the structural changes of Aβ1–42 in water (Aβ-H2O) and the mixed hexafluoroisopropanol (HFIP) with water (Aβ-HFIP/H2O). The mixed solvent consisted of hexafluoroisopropanol (HFIP) and water was used with the ratio of HFIP:H2O (80:20). The effect of zinc ion was also examined for the interaction of Aβ peptide with zinc in water (Aβ-Zn-H2O) and mixed solvent (Aβ-Zn-HFIP/H2O) using all atom level molecular dynamics (MD) calculations for 1 μs. We found that Aβ-Zn-HFIP/H2O contained more α-helix compared to Aβ-HFIP/H2O while Aβ-H2O and Aβ-Zn-H2O produced well-dissolved structure and they contained more β-sheets. β-turns are possible to bind with the receptor proteins and may induce the aggregation process in AD. Thus, Aβ-H2O and Aβ-Zn-H2O have higher possibility leading to AD compared to Aβ-Zn-HFIP/H2O and Aβ-HFIP/H2O models.

HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease.

Alzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases, and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.

Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1–42) aggregates with Ki values of 24 and 4.5nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [125I]2 displayed no clear accumulation toward Aβ plaques in the brain sections of Tg2576 mice, whereas the accumulation pattern of [125I]8 matched with the presence of Aβ plaques both in the brain sections of Tg2576 mice and an AD patient. In biodistribution studies using normal mice, [125I]2 showed preferable in vivo pharmacokinetics (4.82%ID/g at 2min and 0.45%ID/g at 60min), while [125I]8 showed only a modest brain uptake (1.62%ID/g at 2min) with slow clearance (0.56%ID/g at 60min). [125I]8 showed prospective binding properties for Aβ plaques, although further structural modifications are needed to improve the blood brain barrier permeability and washout from brain.

Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition. Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium. We used multivariable logistic regressions to model outcomes [Aβ plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE ε4 (allelic discrimination assay), older age (≥50 years), Aβ plaques, and their two-way interactions] and comorbid factors. Isocortical Aβ deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-ε4 carriers (n = 57). The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally, Aβ plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND patients who could benefit from Aβ-targeted therapies.

APOE4 predicts amyloid-β in cortical brain biopsy but not idiopathic normal pressure hydrocephalus

ObjectiveTo investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-β (Aβ) plaques in cortical brain biopsies of...

Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature.

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Neurologic and motor dysfunctions in APP transgenic mice

The discovery of gene mutations underlying autosomal dominant Alzheimer's disease has enabled researchers to reproduce several hallmarks of this disorder in transgenic mice, notably the formation of Aβ plaques in brain and cognitive deficits. APP transgenic mutants have also been investigated with respect to survival rates, neurologic functions, and motor coordination, which are all susceptible to alteration in Alzheimer dementia. Several transgenic lines expressing human mutated or wild-type APP had higher mortality rates than non-transgenic controls with or without the presence of Aβ plaques. Mortality rates were also elevated in APP transgenic mice with vascular amyloid accumulation, thereby implicating cerebrovascular factors in the precocious death observed in all APP transgenic models. In addition, myoclonic jumping has been described in APP mutants, together with seizure activity, abnormal limb-flexion and paw-clasping reflexes, and motor coordination deficits. The neurologic signs resemble the myoclonic movements, epileptic seizures, pathological reflexes, and gait problems observed in late-stage Alzheimer's disease.