scholarly journals Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tomer Illouz ◽  
Raneen Nicola ◽  
Linoy Ben-Shushan ◽  
Ravit Madar ◽  
Arya Biragyn ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Protein Misfolding ◽  
Short Term Memory ◽  
Amyloid Β ◽  
Maternal Antibodies ◽  
Microglial Phenotype ◽  
Endogenous Protein ◽  
Wild Type Female ◽  
The Central Nervous System ◽  
Protein Misfolding And Aggregation

AbstractMaternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer’s disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-β (Aβ) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aβ overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aβ MAbs might promote the removal of early Aβ accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aβ1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation. MAbs reduce the offspring’s cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the FcγR1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early Aβ deposition, as occurs in EOAD and DS.

scholarly journals Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

2020 ◽  
Author(s):  
Tomer Illouz ◽  
Raneen Nicola ◽  
Linoy Ben-Shuhan ◽  
Ravit Madar ◽  
Arya Biragyn ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Short Term Memory ◽  
Passive Immunization ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Maternal Antibodies ◽  
Dependent Manner ◽  
Short Term ◽  
Wild Type Female ◽  
Potential Strategy

AbstractDown Syndrome (DS) features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation. As DS can be diagnosed in utero, maternally transferred anti-Aβ antibodies might promote removal of early accumulation of Aβ from the CNS. A DNA-vaccine expressing Aβ1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation, similar to individuals with DS. Maternal Aβ-specific antibodies provided transgenic offspring with passive immunization against Aβ via the placental and subsequently lactation. Maternal antibodies reduced cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits and activation of the FcγR1/Syk/Cofilin pathway in microglia. Sera from immunized dams facilitated Aβ clearance by microglia in a Syk-dependent manner. These data suggest that maternal anti-Aβ immunization is a potential strategy to alleviate cognitive decline in individuals with DS.

Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Alessio Crestini ◽  
Francesca Santilli ◽  
Stefano Martellucci ◽  
Elena Carbone ◽  
Maurizio Sorice ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Amyloid Β ◽  
Specific Protein ◽  
Cellular Prion Protein ◽  
Aβ Oligomers ◽  
The Central Nervous System ◽  
Induced Signal

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

scholarly journals Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

2020 ◽  
Vol 53 ◽  
Author(s):  
Tessa Sinnige ◽  
Karen Stroobants ◽  
Christopher M. Dobson ◽  
Michele Vendruscolo
Keyword(s):  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
In Vivo Models ◽  
Disease Modifying Drugs ◽  
Parkinson’S Diseases ◽  
Protein Misfolding And Aggregation

Abstract Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.

scholarly journals Changes in cognitive function in patients with diabetes mellitus

2012 ◽  
Vol 153 (9) ◽  
pp. 323-329 ◽  
Author(s):  
Barbara Szémán ◽  
Géza Nagy ◽  
Tímea Varga ◽  
Anna Veres-Székely ◽  
Mária Sasvári ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Function ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Microvascular Disease ◽  
Aging Brain ◽  
Supporting Evidence ◽  
Patients With Diabetes ◽  
The Central Nervous System ◽  
Psychomotor Efficiency

Patients with diabetes are approximately 1.5 times more likely to experience cognitive decline than individuals without diabetes mellitus. Most of the data suggest that patients with diabetes have reduced performance in numerous domains of cognitive function. In patients with type 1 diabetes, specific and global deficits involving speed of psychomotor efficiency, information processing, mental flexibility, attention, and visual perception seem to be present, while in patients with type 2 diabetes an increase in memory deficits, a reduction in psychomotor speed, and reduced frontal lobe (executive) functions have been found. The complex pathophysiology of changes in the central nervous system in diabetes has not yet been fully elucidated. It is important to consider the patient’s age at the onset of diabetes, the glycemic control status, and the presence of diabetic complications. Neurological consequences of diabetes appear parallel to those observed in the aging brain. Neuroimaging studies highlight several structural cerebral changes, cortical and subcortical atrophy, beside increased leukoaraiosis that occurs in association with diabetes. There is supporting evidence from many hypotheses to explain the pathophysiology of cognitive decline associated with diabetes. The main hypotheses pointing to the potential, implied mechanisms involve hyperglycemia, hypoglycemia, microvascular disease, insulin resistance, hyperinsulinism, hyperphosphorylation of tau protein, and amyloid-β deposition. Orv. Hetil., 2012, 153, 323–329.

scholarly journals Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 132 ◽  
Author(s):  
Neetu Kushwah ◽  
Vishal Jain ◽  
Dhananjay Yadav
Keyword(s):  
Protein Misfolding ◽  
Organic Molecules ◽  
Pathological Condition ◽  
Amyloid Β ◽  
Water Molecules ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Aβ Aggregation ◽  
Protein Misfolding And Aggregation ◽  
The Brain

Most of the neurological disorders in the brain are caused by the abnormal buildup of misfolded or aggregated proteins. Osmolytes are low molecular weight organic molecules usually built up in tissues at a quite high amount during stress or any pathological condition. These molecules help in providing stability to the aggregated proteins and protect these proteins from misfolding. Alzheimer’s disease (AD) is the uttermost universal neurological disorder that can be described by the deposition of neurofibrillary tangles, aggregated/misfolded protein produced by the amyloid β-protein (Aβ). Osmolytes provide stability to the folded, functional form of a protein and alter the folding balance away from aggregation and/or degradation of the protein. Moreover, they are identified as chemical chaperones. Brain osmolytes enhance the pace of Aβ aggregation, combine with the nearby water molecules more promptly, and avert the aggregation/misfolding of proteins by providing stability to them. Therefore, osmolytes can be employed as therapeutic targets and may assist in potential drug design for many neurodegenerative and other diseases.

Cognitive Decline and Treatment Strategies in Multiple Sclerosis Patients

2020 ◽  
pp. 1-7
Author(s):  
Effrosyni Koutsouraki ◽  
Effrosyni Koutsouraki
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Short Term Memory ◽  
Treatment Strategies ◽  
Emotional Disturbances ◽  
Social Impairment ◽  
The Central Nervous System ◽  
Significant Deficit ◽  
Multiple Sclerosis Patients

Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS), mainly appeared in young adults, characterized by neuroinflammation, demyelination, neurodegeneration and remyelination and with a variety of CNS-related symptoms. The prevalence of cognitive decline in MS patients has been reported to range widely, from 13% to 72%, occurring in all stages of the disease, and can lead to mental disability, social impairment, and an impoverished quality of life. The pathogenetic mechanism of the cognitive decline in MS has yet to be revealed, and, thus, we are still unable to predict which patients are more likely to manifest such a decline and at what stage of the disease. Clinical factors, including the type and the course of the disease, but also fatigue and emotional disturbances, can impact the degree of MSrelated cognitive impairment. It has been reported that almost 40% of the MS patients demonstrate a significant deficit in recognizing and recalling verbal and visual memories, either at the onset of the disease or at its later stages, whereas short-term memory remains almost intact. Many patients also demonstrate deficits in complex attention, a slower efficiency in information processing, a declined ability of problemsolving, planning, and prioritization tasks or even visual agnosia and aphasia. Most of the MS-specific disease-modifying treatments seem to reduce the rate of MS attacks and slower the progression; however, their impact on cognitive impairment remains unclear. We propose that cognitive function evaluations should be incorporated in the regular assessment and monitoring of MS patients since they seem to be well correlated with the progression of the disease. Even if the effect of the neuropsychological batteries used for diagnostic and therapeutic purposes still remains very much limited, especially due to the validation and standardization issues, specific cognitive functions treatment strategies should be implemented in the therapeutic scheme of MS patients.

The Use of Neuroplastic Principles Affects the Swallow Motor Plan of a Patient in Severe Cognitive Decline: A Case Study

2016 ◽  
Vol 1 (15) ◽  
pp. 79-83
Author(s):  
Ed Bice ◽  
Kristine E. Galek
Keyword(s):  
Central Nervous System ◽  
Cognitive Decline ◽  
Full Range ◽  
Movement Speed ◽  
Positive Outcomes ◽  
Verbal Cues ◽  
Motor Plan ◽  
Bolus Size ◽  
The Central Nervous System

Dysphagia is common in patients with dementia. Dysphagia occurs as a result of changes in the sensory and motor function of the swallow (Easterling, 2007). It is known that the central nervous system can undergo experience-dependent plasticity, even in those individuals with dementia (Park & Bischof, 2013). The purpose of this study was to explore whether or not the use of neuroplastic principles would improve the swallow motor plan and produce positive outcomes of a patient in severe cognitive decline. The disordered swallow motor plan was manipulated by focusing on a neuroplastic principles of frequency (repetition), velocity of movement (speed of presentation), reversibility (Use it or Lose it), specificity and adaptation, intensity (bolus size), and salience (Crary & Carnaby-Mann, 2008). After five therapeutic sessions, the patient progressed from holding solids in her mouth with decreased swallow initiation to independently consuming a regular diet with full range of liquids with no oral retention and no verbal cues.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oscar Aubi ◽  
Karina S. Prestegård ◽  
Kunwar Jung-KC ◽  
Tie-Jun Sten Shi ◽  
Ming Ying ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Misfolding ◽  
Phenylalanine Hydroxylase ◽  
Hepatic Tissue ◽  
Loss Of Function ◽  
Advantageous Position ◽  
Protein Misfolding And Aggregation ◽  
Activity Decrease ◽  
Systemic Accumulation ◽  
Altered Lipid

AbstractPhenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

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