Recent progress towards vaccines and antibody-based therapies against Alzheimer's disease

2021 ◽  
Vol 21 ◽  
Author(s):  
Wenbo Ji ◽  
Baofeng Gong ◽  
Hong Jin ◽  
Xiaohan Chen ◽  
Peng Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Phase 1 ◽  
Amyloid Β ◽  
Communication Disorders ◽  
Tau Proteins ◽  
Research Progress ◽  
Term Survival ◽  
Clinical Phase

: Alzheimer's disease (AD), one of the progressive neurodegenerative disorders, is featured by clinical features such as memory loss, acquired skill loss, apraxia, and interpersonal and social communication disorders. The AD hallmarks at neuropathological level include intracellular neurofibrillary tangles constituted by the hyperphosphorylated tau protein as well as the senile extracellular plaques dominated by the amyloid-β (Aβ) deposits. At present, AD treatment is mainly targeted towards improving symptoms, and effective drugs to delay or stop disease progression are lacking. vaccines and antibody-based therapies are a type of natural, synthetic, and gene recombinant biological product that treat or prevent disease progression by stimulating specific or non-specific immune responses. Compared with traditional targeted drugs, vaccines and antibody-based therapies have better safety and effectiveness, and can even maintain the expression and stability of Aβ and Tau proteins in patients for a long time. Logically, vaccines and antibody-based therapies are somewhat different from traditional drugs because these drugs can achieve the therapeutic effect of AD by activating immune cells and regulating the immune system of patients themselves, thereby clearing disease-related proteins, and long-term survival or even complete cure is observed in some patients after receiving the immunotherapy. Currently available vaccines and antibody-based therapies mainly target Aβ and phosphorylated tau proteins. There are 44 vaccines and antibody-based therapies for AD, among which nine drugs are discontinued, three drugs are inactive, eleven drugs are in clinical phase 1, twelve drugs are in clinical phase 2, and seven drugs are in clinical phase 3. Currently, no vaccines and antibody-based therapies have been approved for AD treatment. In this paper, we review and analyse the research progress of vaccines and antibody-based therapies that are used to treat AD.

Immune modulations and immunotherapies for Alzheimer’s disease: a comprehensive review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sara Mahdiabadi ◽  
Sara Momtazmanesh ◽  
George Perry ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cognitive Outcomes ◽  
Tau Proteins ◽  
Causal Role ◽  
Wide Range ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Immune Related Genes

Abstract Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.

AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

2018 ◽  
pp. 1-7
Author(s):  
P. Novak ◽  
N. Zilka ◽  
M. Zilkova ◽  
B. Kovacech ◽  
R. Skrabana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Primary Progressive Aphasia ◽  
Tau Proteins ◽  
Active Immunotherapy ◽  
Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

scholarly journals Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chu Hsien Lim ◽  
Prameet Kaur ◽  
Emelyne Teo ◽  
Vanessa Yuk Man Lam ◽  
Fangchen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Biological Effects ◽  
Amyloid Β ◽  
Tissue Loss ◽  
Amyloid Β Peptide ◽  
Physical Damage ◽  
Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults

2019 ◽  
Vol 70 (2) ◽  
pp. 553-562 ◽  
Author(s):  
Chinedu T. Udeh-Momoh ◽  
Bowen Su ◽  
Stephanie Evans ◽  
Bang Zheng ◽  
Shireen Sindi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Amyloid Β ◽  
Cognitively Normal

Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis

2019 ◽  
Vol 19 (2) ◽  
pp. 60-77 ◽  
Author(s):  
Anthony G. Pacholko ◽  
Caitlin A. Wotton ◽  
Lane K. Bekar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Environmental Factors ◽  
Late Onset ◽  
Caloric Intake ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Loss Of Function ◽  
Brain Insulin Resistance ◽  
Perfect Storm

North American incidence of Alzheimer’s disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a “perfect storm” to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.

Research Progress of Alzheimer’s Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis

2020 ◽  
Vol 78 (4) ◽  
pp. 1315-1338
Author(s):  
Xinquan Li ◽  
Weiting Xuan ◽  
Dabao Chen ◽  
Huawu Gao ◽  
Guangyun Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Amyloid Β ◽  
Renin Angiotensin System ◽  
Research Progress ◽  
Signal Peptides ◽  
Amyloid Β Protein ◽  
Angiotensin System ◽  
Renin Angiotensin

It is widely recognized that Alzheimer’s disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD.

scholarly journals Biological Markers in Alzheimer's Disease

2007 ◽  
Vol 34 (S1) ◽  
pp. S72-S76 ◽  
Author(s):  
Peter Bailey
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Sensitivity And Specificity ◽  
Pharmacological Action ◽  
Tau Proteins ◽  
Tissue Samples ◽  
Repeated Sampling ◽  
Markers Of Oxidative Stress ◽  
Diagnostic Sensitivity And Specificity

abstractBiomarkers are required to improve our diagnostic sensitivity and specificity and to monitor the biological activity of the Alzheimer’s disease (AD) in terms of the burden of neural involvement and the tempo of disease progression. Biomarkers will initially supplement our more traditional neuropsychological and imaging markers but may eventually evolve into useful surrogate endpoints in AD research. These markers may also provide important mechanistic clues to the pharmacological action of anti-dementia compounds. At this point, the combination of elevated cerebrospinal fluid phosphorylated TAU (CSF p-TAU) proteins and low CSF A²1-42are the only biomarkers with the sensitivity and specificity to serve as useful diagnostic biomarkers capable of distinguishing AD from other dementias in the early stages. Advances in non CSF tests is urgently required. Markers assessing the progression of disease do not necessarily require the same high disease specificity as diagnostic markers, but need to be sensitive to changes in disease state. At present, candidate markers fall under four main biological rationales: 1. Specific markers of AD neuropathology; 2. Non-specific markers of neural degeneration; 3. Markers of oxidative stress; 4. Markers of neural inflammation. It is foreseeable that a panel of such markers might prove advantageous. It will be important to develop “non-invasive “ markers utilizing readily obtainable tissue samples such as serum or urine to monitor disease progression (or hopefully regression). Repeated sampling would allow for comparison with traditional neuropsychological and imaging measures. The assays themselves will need to be reproducible, reliable and relatively inexpensive. Unfortunately, these biomarkers are in the formative stages of testing and results at present are inconclusive. To facilitate biomarker development in the future it would be highly advantageous to begin to collect and store biological specimens as an adjunct to current research in AD.

scholarly journals Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

1995 ◽  
Vol 306 (2) ◽  
pp. 599-604 ◽  
Author(s):  
E M Castano ◽  
F Prelli ◽  
T Wisniewski ◽  
A Golabek ◽  
R A Kumar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Tau Proteins ◽  
Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

scholarly journals The coupling of global brain activity and cerebrospinal fluid inflow is correlated with Alzheimer’s disease related pathology

2020 ◽  
Author(s):  
Feng Han ◽  
Jing Chen ◽  
Aaron Belkin-Rosen ◽  
Yameng Gu ◽  
Liying Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Driving Forces ◽  
Brain Activity ◽  
Amyloid Β ◽  
Resting State Fmri ◽  
High Amplitude ◽  
Tau Proteins ◽  
Global Brain

AbstractThe glymphatic system plays an important role in clearing the amyloid-β and tau proteins that are closely linked to Alzheimer’s disease (AD) pathology. Glymphatic clearance, as well as amyloid-β accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state fMRI, is coupled with the CSF movements, suggesting their potential link to the glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical amyloid-β level, and the cognitive decline over a two-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

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