Aβ Amyloid Deposition Research Articles

Research on the pathogenesis of Alzheimer's disease based on thalamocortical computational model.

Alpha rhythm slowing is an important electroencephalogram(EEG) feature associated with (AD). This study aims to understand the correlation between alpha band deceleration and molecular changes from the perspective of neural computing. Considering the effect of Aβ amyloid deposition on the inhibitory changes in the thalamic, a thalamic cortical model coupled with Aβ amyloid is established. The results show that Aβ amyloid deposition may induce neurotoxicity in thalamic reticular nucleus neurons, which results in inhibitory changes in the thalamus and slows the alpha rhythm of EEG output from the thalamus. In order to understand the pathogenesis more intuitively, some numerical simulations are provided to illustrate the obtained theories. This research is helpful to understand the pathogenesis of AD, so as to provide theoretical basis for the intervention and control of the disease.

The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease.

Neuroinflammation has been identified as another significant pathogenic factor in Alzheimer's disease following Aβ amyloid deposition and tau protein hyperphosphorylation, activated in the central nervous system by glial cells in response to injury-related and pathogen-related molecular patterns. Moderate glial cell activity can be neuroprotective; however, excessive glial cell activation advances the pathology of Alzheimer's disease and is accompanied by structural changes in the brain interface, with peripheral immune cells entering the brain through the blood-brain barrier, creating a vicious circle. The immunomodulatory properties of mesenchymal stem cells (MSCs) are primarily conveyed through extracellular vesicles (EVs). MSC-EVs participate in chronic inflammatory and immune processes by transferring nucleic acids, proteins and lipids from the parent cell to the recipient cell, thus MSC-EVs retain their immunomodulatory capacity while avoiding the safety issues associated with living cell therapy, making them a promising focus for immunomodulatory therapy. In this review, we discuss the modulatory effects of MSC-EVs on Alzheimer's disease-associated immune cells and the mechanisms involved in their treatment of the condition. We have found a clinical trial of MSC-EVs in Alzheimer's disease treatment and outlined the challenges of this approach. Overall, MSC-EVs have the potential to provide a safe and effective treatment option for Alzheimer's disease by targeting neuroinflammation.

5‐LOX: blood based biomarker for Alzheimer’s disease (AD) and effect of peptide inhibitor on neurotoxicity developed in AD.

AbstractBackgroundThe inflammatory process plays a key role in neurodegenerative disorder. Pro‐inflammatory molecule, 5‐Lipooxygenase (5‐LOX), protein is involved in pathologic phenotype of AD. It includes Aβ amyloid deposition and tau hyper phosphorylation both but the detail mechanism is still illusive. This study determined the level of 5‐LOX in serum of Alzheimer’s disease (AD) patient, Mild cognitive impairment (MCI), normal elderly and rescue effect by YWCS, a peptide inhibitor of 5‐LOX on neurotoxicity by Aβ amyloid (Aβ25‐35) in neuroblastoma cells SH‐SY5Y.MethodThe level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.ResultThe level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.ConclusionThe differential expression of serum 5‐LOX among the study groups suggests, it can be one of potential serum protein marker and therapeutic regimen for AD and MCI. Peptide YWCS, can serve as new platform as 5‐LOX inhibitor which can prevent neurotoxicity developed in AD.

Association of Alzheimer's dementia with oral bacteria, vitamin B12, folate, homocysteine levels, and insulin resistance along with its pathophysiology, genetics, imaging, and biomarkers

Alzheimer's disease is a prevalent form of dementia, particularly among the elderly population. It is characterized by progressive cognitive decline and neurodegeneration. Despite numerous studies, the exact cause of Alzheimer's disease remains uncertain, and various theories have been proposed, including Aβ amyloid deposition in the brain and tau protein hyper-phosphorylation. This review article explores the potential pathogenesis of Alzheimer's disease, focusing on the effects of derangements in the levels of vitamin B12, folate, and homocysteine, as well as the impact of oral bacteria causing periodontitis and insulin resistance, and their relationship to Alzheimer's. Studies have shown that high levels of homocysteine and low levels of vitamin B12 and folate, are associated with an increased risk of developing Alzheimer's disease. The article also explores the link between Alzheimer's disease and oral bacteria, specifically dental infections and periodontitis, which contribute to the inflammatory processes in the nervous system of Alzheimer's patients. There could be derangement in the insulin signaling further causing disruption in glucose metabolism within the brain, suggesting that Alzheimer's disease may represent a form of type 2 diabetes mellitus associated with the brain, commonly known as type 3 diabetes. Neuroimaging techniques, including MRI, PET, and tau PET, can identify the predictive characteristics of Alzheimer's disease, with amyloid PET being the most useful in ruling out the disease. The article concludes by stressing the importance of understanding genetic and neuroimaging factors in the diagnosing and treating Alzheimer's disease.

Protective effect of Lactococcus laudensis and Pediococcus parvulus against neuropathy due to amyloid-beta in Caenorhabditis elegans

In Alzheimer’s disease (AD), the amyloid-β (Aβ) protein begins to accumulate in the brain 20 years prior to any dementia symptoms manifestation, in which Aβ aggregates in the brain, causing destruction of nerve cells and resulting in memory impairments. Lifestyle and diet appear to inhibit Aβ production and amyloid deposition. Therefore, identifying factors that prevent Aβ production and administering them before the onset of AD, may be an effective preventive method. Lactic acid bacteria (LAB) exhibit various health effects on the host and are expected to have protective effects on neurological functions via brain-gut correlation. However, the protective effects of LAB against Aβ are not well understood. We investigated whether LAB feeding could ameliorate the toxicity of Aβ peptide accumulation in transgenic Caenorhabditis elegans expressing the human Aβ peptide in neurons or muscle as an AD model. Aβ expressed in muscle caused myopathy and worm paralysis, while Aβ in neurons disturbed chemotactic activity. Among 14 screened strains, Lactococcus laudensis (LL) and Pediococcus parvulus (PP) prevented the AD worms from losing their chemotaxis behavior and becoming paralyzed by the Aβ peptide. Immunostaining and western blotting indicated that Aβ peptide was significantly suppressed in worms fed these two strains, and binding of the Aβ to vitellogenin was particularly inhibited. Conversely, the mRNA level of the Aβ gene did not change between LL- or PP-fed worms and the control. In conclusion, LL and PP alleviate neurotoxicity by inhibiting Aβ accumulation; AD model worms can be used to screen efficient LAB for AD prevention.

Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer’s disease

BackgroundWith a growing number of loci associated with late-onset (sporadic) Alzheimer’s disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility.ResultsUsing genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset.ConclusionOverall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone.

Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model.

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.

Connectivity and Patterns of Regional Cerebral Blood Flow, Cerebral Glucose Uptake, and Aβ-Amyloid Deposition in Alzheimer's Disease (Early and Late-Onset) Compared to Normal Ageing.

The aim of this study was to investigate the differences in early (EOAD) and late (LOAD) onset of Alzheimer´s disease, as well as glucose uptake, regional cerebral blood flow (R1), amyloid depositions, and functional brain connectivity between normal young (YC) and Old Controls (OC). The study included 22 YC (37 ± 5 y), 22 OC (73 ± 5.9 y), 18 patients with EOAD (63 ± 9.5 y), and 18 with LOAD (70.6 ± 7.1 y). Patients underwent FDG and PIB PET/CT. R1 images were obtained from the compartmental analysis of the dynamic PIB acquisitions. Images were analyzed by a voxel-wise and a VOI-based approach. Functional connectivity was studied from the R1 and glucose uptake images. OC had a significant reduction of R1 and glucose uptake compared to YC, predominantly at the dorsolateral and mesial frontal cortex. EOAD and LOAD vs. OC showed a decreased R1 and glucose uptake at the posterior parietal cortex, precuneus, and posterior cingulum. EOAD vs. LOAD showed a reduction in glucose uptake and R1 at the occipital and parietal cortex and an increased at the mesial frontal and temporal cortex. There was a mild increase in an amyloid deposition at the frontal cortex in LOAD vs. EOAD. YC presented higher connectivity than OC in R1 but lower connectivity considering glucose uptake. Moreover, EOAD and LOAD showed a decreased connectivity compared to controls that were more pronounced in glucose uptake than R1. Our results demonstrated differences in amyloid deposition and functional imaging between groups and a differential pattern of functional connectivity in R1 and glucose uptake in each clinical condition. These findings provide new insights into the pathophysiological processes of AD and may have an impact on patient diagnostic evaluation.

Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5–77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6–70.3); however, noncarriers reached the threshold later at age 78 (76.1–84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.

Induction of p73, Δ133p53, Δ160p53, pAKT lead to neuroprotection via DNA repair by 5-LOX inhibition

The inflammatory process plays a key role in neurodegenerative disorder. The inflammatory molecule, 5-lipooxygenase (5-LOX), protein is involved in the pathologic phenotype of AD which includes Aβ amyloid deposition and tau hyperphosphorylation. This study aims to identify the mechanistic role in neuroprotection by 5-LOX inhibitor in neurotoxic SH-SY5Y cell line model by evaluating different cell survival pathway. The neurotoxic SH-SY5Y cells were developed by the treatment of Aβ25-35. The cells were then treated with 5-LOX peptide inhibitor, YWCS to prevent neurotoxicity reported earlier from our lab. The effect of 5-LOX inhibition on cell survival pathways were determined by western blot experiment with different doses of peptide by using polyclonal anti body of p53, anti-Akt and anti-phosphorylated Akt. Immunoprecipitation and mass spectroscopic studies were done to identify the altered proteins appeared on the blot. Over expression of phosphorylated Akt and 3 bands on p53 lane blot other than p53 were observed. Three bands were identified as isoforms of p53 which correspond to p73, Δ133p53 and Δ160p53 in the cells treated only with 80µM of YWCS compare to untreated cells. However, no alteration of total p53 and Akt were observed in treated cells. The results exposed the novel mechanistic pathway of neuroprotection by 5-LOX inhibition is likely to be mediated by DNA DSB repair through p53 isoforms and PI3K/Akt pathway. Our finding has opened a new window in the therapeutic approach for the prevention of AD.

ASSESSING GLOBAL AND REGIONAL Aβ-AMYLOID DEPOSITION IN THE BRAIN WITH MULTIPLE Aβ-TRACERS USING THE CENTILOID SCALE

The aim of the study was to evaluate if Centiloids (CL) generated with different Aβ tracers yielded similar rates of Aβ accumulation, validating its use in multicenter, multitracer anti-Aβ therapeutic trials. We used longitudinal Aβ imaging data from the AIBL and ADNI studies to calculate the rates of global and regional Aβ-amyloid deposition. We analyzed 485 participants from AIBL and ADNI (321 HC; 135 MCI; 29 AD) with 3 or more Aβ imaging assessments. While AIBL participants underwent Aβ imaging with PiB and NAV4694 (n=220, median follow-up of 4.8 –range 2.5-10.6– years), or flutemetamol (FLUTE, n=94, median follow-up of 3.2 –range 3.0-3.8– years), ADNI participants underwent Aβ imaging with florbetapir (FBP, n=171, median follow-up of 4.1 –range 2.9−5.7 – years). CL were generated using the standard CL cortical and whole cerebellum masks. FBP SUVR were first generated using a white matter mask and then converted to whole cerebellum before the CL transformation. Aβ accumulation was derived from the slope of the linear regression plots, and rates of accumulation were calculated from the time it took to go from a threshold 20 CL (Aβ-) to 100 CL (mean levels of Aβ+AD). Of 485 initial participants, 417 (86%) (270 HC; 118 MCI; 29 AD) showed positive rates of Aβ accumulation over 3 or more assessments. Irrespective of the Aβ tracer used, Aβ deposition spans more than two decades, averaging 22.7±3.9 (mean±SD) years to go from a threshold of 20 CL to 100 CL. Rates of Aβ accumulation were 3.8 CL/yr (5%/yr) for PiB/NAV, 3.6 CL/yr (5%/yr) for FLUTE and 3.0 CL/yr (4%/yr) for FBP, respectively, averaging 3.5±0.4 CL/yr (4.3%/yr) when all tracers are considered together. The regional assessment showed fastest Aβ accumulation in the posterior cingulate/precuneus and frontal areas, and slowest in the hippocampus. Aβ-amyloid deposition is a slow and protracted process, extending for more than two decades. Centiloids can be used to combine longitudinal Aβ imaging data obtained with different Aβ tracers.

Cardiac Abnormalities in Alzheimer Disease: Clinical Relevance Beyond Pathophysiological Rationale and Instrumental Findings?

ObjectivesThis case control study sought to assess the presence and characteristics of cardiac abnormalities in patients with Alzheimer disease (AD). BackgroundProtein misfolding is involved in the pathophysiology of neurodegenerative disorders such as AD. Recently, amyloid-beta (Aβ) aggregates were identified within the cardiomyocytes and interstitium of patients with AD, suggesting that Aβ oligomers may reach and damage the heart. MethodsThe authors studied 32 patients with AD and 34 controls matched by age and sex, all of whom were free from cardiac or systemic diseases. A clinical evaluation, an electrocardiogram, and an echocardiogram were performed in all subjects. Furthermore, patients with AD underwent genetic analyses (of the PSEN1, PSEN2, APP, and APOE genes). ResultsCompared to the control group, patients with AD had a higher prevalence of low-voltage electrocardiographic QRS complexes (28% vs. 3%, respectively; p = 0.004), a lower voltage/mass ratio (p = 0.05), a greater echocardiographic interventricular septum (10.1 ± 1.3 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.01), a greater maximum wall thickness (10.8 ± 1.7 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.0001), and a 2-fold higher prevalence of diastolic dysfunction (70% vs. 35%, respectively; p = 0.007). Symptoms and signs of heart failure were absent in all patients with AD. ConclusionsThis study shows that electrocardiographic and echocardiographic abnormalities, including diastolic dysfunction, are present in patients with AD and that these studies reproduce the pattern of cardiac amyloidosis. These findings suggest that, in AD, there may be subclinical cardiac involvement likely associated with Aβ amyloid deposition. The clinical relevance of these cardiac abnormalities should be evaluated in larger prospective studies.

Apolipoprotein E and clusterin inhibit the early phase of amyloid-\u03b2 aggregation in an in vitro model of cerebral amyloid angiopathy

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA.

THE IMPACT OF APOE ε4 CARRIAGE ON Aβ-AMYLOID DEPOSITION IN AIBL

APOE-ε4 carriage is the main genetic risk factor for Alzheimer's. However, how ε4 carriage affects pathological changes remains unclear. We have attempted to elucidate the impact of ε4 carriage on Aβ-amyloid deposition. 194 AIBL participants (86 ε4 carriers [72.22±7.21] and 108 non ε4 carriers [72.29±7.43]) with a mean follow-up of 6.12±2.00 years were analysed. The odds ratio and NPV/PPV statistics for the progression of normal controls (NC) to MCI/AD for ε4 carriers vs non-carriers were calculated. Further, the natural history of deposition of Aβ-amyloid was estimated for ε4 carriers and non-carriers using a 4-step procedure [1,2]. Kaplan-Meier statistics were used to estimate the prevalence of abnormal levels of Aβ-amyloid by age for ε4 carriers and non-carriers. NC ε4 carriers are twice as likely (OR 2.21) to progress to MCI or AD in comparison to non-carriers. While there were no significant differences in the rates of Aβ-amyloid deposition between ε4 carriers and non-carriers (Fig 1), ε4-carriers have an earlier onset for abnormal levels of Aβ-amyloid deposition (∼15 years, Fig 1 & Fig 2).

CHEMICALLY TREATED PLASMA Aβ AND ACETYLCHOLINESTERASE LEVELS ARE POTENTIAL BIOMARKERS FOR PREDICTION OF PIB-PET POSITIVITY IN THE BRAIN

Blood-based biomarkers have been extensively studied for many diseases due to accessibility and convenience. Plasma β-Amyloid (Aβ) has been a potential candidate for an Alzheimer's disease (AD) biomarker although it is controversial, and many researchers are still investigating the relationship between plasma Aβ and brain amyloid deposition. Brain acetylcholinesterase (AchE) is another key factor closely related to AD because cholinergic neurons are the main victim during AD pathogenesis. Cross-sectional study of 374 participants (212 cognitively normal, 104 mild cognitive impairment, and 58 AD dementia) with Pittsburgh-compound B PET (PiB-PET) imaging data was performed. We discovered a special treatment of protease inhibitors and phosphatase inhibitors (MPP) novel method for stabilized detection of plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) using X-map technology. Also, we compared plasma AchE protein levels from same 374 participants above in MPP-Aβs measurement, and AchE levels were measured by ELISA. MPP-Aβ42/40 (MPP-Aβs) levels in plasma showed significant reduction in positive amyloid deposition (PiB+) patients compared with subjects with PiB negative amyloid deposition (PiB-) (***P < 0.0001), and we discovered the significant increase of plasma AchE level in PiB+ compared to PiB-. Also, both MPP-Aβ42/40 and AchE represented significant correlation with PiB retention values (SUVR). Furthermore, combined detection of MPP-Aβ42/40 level with AchE level in plasma indicate brain Aβ accumulation positivity better than one factor either MPP-Aβ42/40 level or AchE level (***P < 0.001). ROC curve represented increased AUC values in combined detection of MPP-Aβ42/40 level with AchE level. We propose that plasma MPP-Aβ and AchE can be used as potential blood biomarkers for prediction of PiB-PET positivity in the brain.

5-LOX in Alzheimer's Disease: Potential Serum Marker and In Vitro Evidences for Rescue of Neurotoxicity by Its Inhibitor YWCS.

The inflammatory process plays a key role in neurodegenerative disorder. The inflammatory molecule, 5-lipooxygenase (5-LOX), protein is involved in the pathologic phenotype of Alzheimer's disease (AD) which includes Aβ amyloid deposition and tau hyperphosphorylation. This study determined the level of 5-LOX in serum of AD patients, mild cognitive impairment (MCI) patients, and the normal elderly, and the rescue effect by YWCS, a peptide inhibitor of 5-LOX on neurotoxicity by Aβ amyloid25-35 (Aβ25-35) in neuroblastoma cells. The concentration of serum 5-LOX was estimated by surface plasmon resonance and western blot. The neuroprotective effect of 5-LOX peptide inhibitor YWCS in Aβ25-35-induced neurotoxicity was analyzed by MTT assay and western blotting. We found significant upregulated serum 5-LOX in AD patients and also in MCI patients compared to the normal control group. The peptide inhibitor of 5-LOX, YWCS, prevented the neurotoxic effect of Aβ25-35 by reducing the expression of γ-secretase as well as p-Tau181 in SH-SY5Y cells. However, YWCS was nontoxic towards normal HEK cells. The differential expression of serum 5-LOX among the study groups suggests it can be one of potential serum protein marker and a therapeutic regimen for AD and MCI. The negative correlation with neuropsychological parameters, i.e., MoCA and HMSE, increases its importance and makes it useful during the clinical setup which is very needful in developing countries. Peptide YWCS can serve as a new platform as a 5-LOX inhibitor which can prevent neurotoxicity developed in AD.

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2.

BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years. We and others have shown that BACE1 is not only a critical enzyme for testing the “Amyloid Hypothesis” associated with Alzheimer’s pathogenesis, but also important for various functions such as axon growth and pathfinding, astrogenesis, neurogenesis, hyperexcitation, and synaptic plasticity. BACE2 appears to play different roles such as glucose homeostasis and pigmentation. This knowledge regarding BACE1 functions is critical for monitoring the safe use of BACE1 inhibitors in humans.

A human monoclonal IgG that binds aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo.

Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aβ and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aβ and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aβ in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aβ amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.

Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review.

Varying degrees of cortical amyloid deposition are reported in the setting of Parkinsonism with cognitive impairment. We performed a systematic review to estimate the prevalence of Alzheimer disease (AD) range cortical amyloid deposition among patients with Parkinson's disease with dementia (PDD), Parkinson's disease with mild cognitive impairment (PD-MCI) and dementia with Lewy bodies (DLB). We included amyloid positron emission tomography (PET) imaging studies using Pittsburgh Compound B (PiB). We searched the databases Ovid MEDLINE, PubMed, Embase, Scopus, and Web of Science for articles pertaining to amyloid imaging in Parkinsonism and impaired cognition. We identified 11 articles using PiB imaging to quantify cortical amyloid. We used the metan module in Stata, version 11.0, to calculate point prevalence estimates of patients with "PiB-positive" studies, that is, patients showing AD range cortical Aβ-amyloid deposition. Heterogeneity was assessed. A scatterplot was used to assess publication bias. Overall pooled prevalence of "PiB-positive" studies across all three entities along the spectrum of Parkinson's disease and impaired cognition (specifically PDD, PD-MCI, and DLB) was 0.41 (95% confidence interval [CI], 0.24-0.57). Prevalence of "PiB-positive" studies was 0.68 (95% CI, 0.55-0.82) in the DLB group, 0.34 (95% CI, 0.13-0.56) in the PDD group, and 0.05 (95% CI, -0.07-0.17) in the PD-MCI group. Substantial variability occurs in the prevalence of "PiB-positive" studies in subjects with Parkinsonism and cognitive impairment. Higher prevalence of PiB-positive studies was encountered among subjects with DLB as opposed to subjects with PDD. The PD-MCI subjects showed overall lower prevalence of PiB-positive studies than reported findings in non-PD-related MCI. © 2015 International Parkinson and Movement Disorder Society.

Imaging Amyloidopathy in Parkinson Disease and Parkinsonian Dementia Syndromes.

Dementia arising in patients with Parkinson disease or parkinsonian neurodegeneration comprises a heterogeneous neuropathology. Clinical labeling of patients with both dementia and Parkinson disease is dichotomous, depending on the temporal development of cognitive impairment and motor parkinsonism. Patients with dementia arising first (or within the first year of PD) are classified as dementia with Lewy bodies; patients with PD for more than one year before cognitive decline are classified as Parkinson disease with dementia. Despite this differential clinical classification, autopsy studies demonstrate variable admixtures of cortical synuicleinopathy, Aβ-amyloidopathy and tau neurofibrillary tangle deposition. There are no routine clinical diagnostic measures that accurately distinguish the underlying neuropathologies in individual patients. In the present paper, we review the published literature describing characteristics of fibrillary Aβ-amyloid deposition on the basis of PET radiotracer imaging in patients with Parkinson disease and in parkinsonian dementia syndromes. Although individual reports often include only small-to-modest subject numbers, there is overall suggestion that PD patients have a lower incidence of Aβ-amyloid deposition than seen amongst elderly normal subjects, and that Parkinson disease with dementia patients have a lower incidence of Aβ-amyloid deposition than do patients with dementia with Lewy bodies. These apparent features contrast the findings of Aβ-amyloid-PET imaging in normal aging and the development of Alzheimer disease, where Aβ-amyloid deposition arises asymptomatically and apparently many years before development of signs or symptoms of dementia. It is proposed that focused, prospective studies are needed to further address and understand the complex role(s) of Aβ-amyloid pathology in Parkinson disease, and that this understanding will be critical to the development of targeted disease-modifying therapy for dementia in PD.