Alzheimer's Disease R&D Review
27.6K views | +7 today
Follow
 
Rescooped by Krishan Maggon from Amazing Science
onto Alzheimer's Disease R&D Review
Scoop.it!

Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus

Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus | Alzheimer's Disease R&D Review | Scoop.it

The concept of a viral role in Alzheimer’s disease (AD), specifically of herpes simplex virus type 1 (HSV1), was first proposed several decades ago (Ball, 1982; Gannicliffe et al., 1986). Legitimizing the concept clearly depended on a positive answer to a number of test questions, the first of which was whether or not HSV1 is ever present in human brain. The subsequent discovery that HSV1 DNA resides in a high proportion of brains of elderly people in latent form (Jamieson et al., 1991)—both normals and AD patients—immediately made the concept more credible, but raised associated questions such as whether or not the virus is ever active in brain or is merely a passive resident there; whether on its own it is a causative factor in AD or it acts thus only with another factor, perhaps genetic; if active, what causes its activity; whether there is any link with the characteristic abnormal features of AD brains or their components, and whether, if indeed implicated in AD, antiviral agents would be useful for treating the disease. These questions were posed in a previous review (Wozniak and Itzhaki, 2010)—and strong evidence was presented that permitted the answer to each question to be “yes” or, very likely to be “yes”. The present review briefly summarizes the earlier evidence, and provides an update, which is especially timely in view of the subsequent steady increase in number of relevant publications.


Herpes simplex virus type 1 (HSV1), when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in Alzheimer’s disease (AD). It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD.


Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau)—changes found to occur in HSV1-infected cell cultures.


Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localized in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors (TLRs) in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain.


Several epidemiological studies have now shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as intravenous immunoglobulin (IVIG).


Via Dr. Stefan Gruenwald
Krishan Maggon 's insight:

Thanks Dr. Gruenwald.

more...
No comment yet.
Alzheimer's Disease R&D Review
A review of the Solanezumab (Lilly), Gantenerumab (Roche) the 2  beta amyloid monoclonal antibodies  in Phase III trials and other potential targets is provided. The failure of Bapineuzumab in Phase III trials in 2012 puta question mark on the validity of beta amyloid hypothesis. Bapineuzumab is a fully humanized monoclonal antibody which targets beta amyloid protein involved in Alzheimer's Disease. There are 26 million patients in the world, half in Asia and the rest in N America/Europe with AD.
Curated by Krishan Maggon
Your new post is loading...
Your new post is loading...
Scooped by Krishan Maggon
Scoop.it!

Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review"

Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review" | Alzheimer's Disease R&D Review | Scoop.it
Krishan Maggon published version 237 of a knol titled: "Bapineuzumab (Pfizer, J&J, Elan) Review"...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease | Alzheimer's Disease R&D Review | Scoop.it
Wang et al. show that delta-secretase phosphorylation by SRPK2 promotes its cytoplasmic
translocation and enzymatic activities. The unphosphorylated mutant rescues AD-like
pathologies, implicating its potential therapeutic role in AD.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis

The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis | Alzheimer's Disease R&D Review | Scoop.it
Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE–complexin–synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE–complexin–synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale.
Krishan Maggon 's insight:
The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis 

 Qiangjun Zhou, Peng Zhou, Austin L. Wang, Dick Wu, Minglei Zhao, Thomas C. Südhof & Axel T. Brunger

Nature (2017) doi:10.1038/nature23484 
Published online 16 August 2017
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Linking Amyloid-β and Tau Deposition in Alzheimer Disease

Linking Amyloid-β and Tau Deposition in Alzheimer Disease | Alzheimer's Disease R&D Review | Scoop.it
Deposition of abnormal or misfolded proteins, amyloid-β (Aβ) into plaques and hyperphosphorylated tau as paired helical filaments and eventually neurofibrillary
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

How to map the circuits that define us

How to map the circuits that define us | Alzheimer's Disease R&D Review | Scoop.it
Neuroscientists want to understand how tangles of neurons produce complex behaviours, but even the simplest networks defy understanding.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Wendy Mitchell: I have dementia and I take part in research. Here’s why – The BMJ

Wendy Mitchell: I have dementia and I take part in research. Here’s why – The BMJ | Alzheimer's Disease R&D Review | Scoop.it
Wendy Mitchell, who has young onset dementia, writes about taking part in dementia research, being valued, and opportunities to change the future. Imagine being given a diagnosis of young onset [...]More...
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Alpha‐synuclein triggers T‐cell response. Is Parkinson's disease an autoimmune disorder?

Alpha‐synuclein triggers T‐cell response. Is Parkinson's disease an autoimmune disorder? | Alzheimer's Disease R&D Review | Scoop.it
Click on the article title to read more.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Parkinson's Disease an Autoimmune Condition

Parkinson's Disease an Autoimmune Condition | Alzheimer's Disease R&D Review | Scoop.it
Technology Networks is an internationally recognised publisher that provides access to the latest scientific news, products, research, videos and posters.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

vTv Therapeutics RAGE inhibitor Azeliragon for Alzheimer disease

vTv Therapeutics RAGE inhibitor Azeliragon for Alzheimer disease | Alzheimer's Disease R&D Review | Scoop.it

Overview


Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE).


RAGE is an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery (Yan et al., 1996; Schmidt et al., 2009), RAGE is found on the cells of the neurovascular compartment: endothelial cells and microglia prominently express RAGE whose expression is upregulated in AD (Yan et al., 2007; Yan et al, 2009). RAGE ligands include Aβ, S100b, HMGB1, and Advanced Glycation Endproducts (AGEs). RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation, and AD (Stern et al., 2002; Bierhaus et al., 2005). RAGE has been proposed to contribute to AD pathology by: promoting vascular leakage, promoting influx of peripheral Aβ into brain; mediating Aβ induced oxidative stress, mediating AGE induced hyperphosphorylation of tau (Li et al., 2011) and Aβ mediated neuronal death (Deane et al., 2003; Carrano et al., 2011; Hartz et al., 2012; Kook et al., 2012; Li et al., 2011).


The pleiotropic role of RAGE in AD pathology has been described using rodent models. RAGE is thought to be involved in the transport of Aβ from peripheral to central nervous system compartments (Tanzi et al., 2004).


Additionally, RAGE is believed to be involved in mediating advanced glycation endproduct induced tau hyperphosphorylation (Li et al., 2011). In vivo, injection of advanced glycation endproducts induced tau hyperphosphorylation, memory deterioration, decline of synaptic proteins and impairment of long-term potentiation. These effects are attenuated following blockade of the RAGE receptor with a RAGE antibody.

Krishan Maggon 's insight:
inhibition of RAGE with an orally available small molecule inhibitor presents an attractive therapeutic rationale for the treatment of Alzheimer’s disease.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

NILVAD – new treatment in Alzheimer's disease

NILVAD – new treatment in Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it

NILVAD – a EC-funded phase III clinical trial of nilvadipine in Alzheimer’s disease


On January 1, 2012 the international European research project NILVAD (A European multicentre double-blind placebo-controlled phase III trial of nilvadipine in mild to moderate Alzheimer’s disease) started, coordinated by the Trinity College Dublin, Ireland. The European Commission funds NILVAD for five years, with an amount of 6 million Euros. Alzheimer’s disease (AD) is an ever-increasing public health concern among the aging population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (www.alz.org, 2010).

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Alzheimer's disease: will cost healthcare $1.1 trillion by 2050

Alzheimer's disease: will cost healthcare $1.1 trillion by 2050 | Alzheimer's Disease R&D Review | Scoop.it


BioPharma


Alzheimer's disease is estimated to cost the healthcare system $1.1 trillion by 2050. Effective disease modifying treatment, while notoriously hard, is a growing necessity. 


 From a look at the ten compounds in Phase 3 trials to an interview with Genentech’s global head of neuroscience and ophthalmology business development, BioPharma Dive explores what you need to know about the science and business of Alzheimer's disease: http://dive.pub/2vbX2QJ

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease

Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it
Highlights • ApoE transcriptionally represses PPP2R5E, a regulatory B′ subunit of protein phosphatase 2A. • ApoE triggers demethylation of the catalytic subunit (PP2AC) of PP2A. • Together, this results in the disruption of the PPP2R5E-PP2AC complex and in PP2A activity. • Our work linking ApoE to a reduction in the PP2A activity has implications for Alzheimer's disease.
Krishan Maggon 's insight:
Molecular and Cellular Neuroscience Volume 83, September 2017, Pages 83-91


more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

A New Insight into Parkinson’s Disease Protein

A New Insight into Parkinson’s Disease Protein | Alzheimer's Disease R&D Review | Scoop.it
New research by UCSF neuroscientist Robert Edwards has uncovered the role alpha-synuclein plays in the normal brain. The protein has long been implicated in Parkinson’s disease.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease | Alzheimer's Disease R&D Review | Scoop.it
The Alzheimer’s disease risk factor TREM2 regulates microglial function through modulation
of cellular biosynthetic metabolism.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells

Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells | Alzheimer's Disease R&D Review | Scoop.it
Sloan et al. developed a method for generating and purifying astrocytes from 3D cerebral
cortical spheroids derived from human pluripotent cells. Long-term culture (∼20 months
in vitro) and direct comparison to human primary cells reveal transcriptional and
functional astrocyte maturation.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

China launches brain-imaging factory

China launches brain-imaging factory | Alzheimer's Disease R&D Review | Scoop.it

Hub aims to make industrial-scale high-resolution brain mapping a standard tool for neuroscience


A huge facility set to open in Suzhou, China, next month should transform high-resolution brain mapping, its developers say. Where typical laboratories might use one or two brain-imaging systems, the new facility boasts 50 automated machines that can rapidly slice up a mouse brain, snap high-definition pictures of each slice and reconstruct those into a 3D picture. This factory-like scale will “dramatically accelerate progress”, says Hongkui Zeng, a molecular biologist at the Allen Institute for Brain Science in Seattle, Washington, which is partnering with the centre. “Large-scale, standardized data generation in an industrial manner will change the way neuroscience is done,” she says. 


 The institute, which will also image human brains, aims to be an international hub that will help researchers to map neural connectivity for everything from studies of Alzheimer’s disease to brain-inspired artificial-intelligence projects, says Qingming Luo, a researcher in biomedical imaging at the Huazhong University of Science and Technology (HUST) in Wuhan, China. Luo leads the new facility, called the HUST-Suzhou Institute for Brainsmatics, which has a 5-year budget of 450 million yuan (US$67 million) and will employ some 120 scientists and technicians. Luo, who calls himself a “brainsmatician”, also built the institute’s high-speed brain-imaging systems.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

New Neuron Types Identified Epigenetically | GEN

New Neuron Types Identified Epigenetically | GEN | Alzheimer's Disease R&D Review | Scoop.it
Single-cell methylomics finds “brain parts” missed by single-cell transcriptomics
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology | Alzheimer's Disease R&D Review | Scoop.it
Highlights • Cancer and AD are two of the major diseases associated aging. • Tau-mediated neurofibrillary tangle and Aβ-mediated senile plaque are the major lesions of AD. • Multiple cell signaling governing tumorigenesis are associated with pathological lesions of AD. • Cancer-related pathways will become promising options for anti-aging and AD treatment.
Krishan Maggon 's insight:
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Volume 1868, Issue 2, December 2017, Pages 341-358
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Miniature lab-grown brains made from stem cells could one day halt damage caused by Alzheimer's -- Sott.net

Miniature lab-grown brains made from stem cells could one day halt damage caused by Alzheimer's -- Sott.net | Alzheimer's Disease R&D Review | Scoop.it
Miniature human brains made from human skin cells could be used to halt the damage caused by Alzheimer's disease in the future. The tiny organs are being grown in a laboratory by British scientists who believe they will one day be able t
more...
No comment yet.
Rescooped by Krishan Maggon from NeuroImmunology
Scoop.it!

Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases

Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases | Alzheimer's Disease R&D Review | Scoop.it
Stem cell‐based therapies for neurodegenerative diseases aim at halting clinical deterioration by regeneration and by providing local support for damaged tissue. Mesenchymal stem cells (MSCs) hol

Via Gilbert C FAURE
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

What do we know about the amyloid theory for Alzheimer's?

What do we know about the amyloid theory for Alzheimer's? | Alzheimer's Disease R&D Review | Scoop.it


BioPharma


The modern era of AD research began about four decades ago, anchored by the discovery of beta-amyloid and tau proteins and the roles they play in the progression of the illness. More recently, investigators have recognized gene therapy and agents non-pathogenic mechanisms of action (MOAs) as possible avenues for AD treatment. Some drugmakers were even able to bring medicines that alleviate AD symptoms to market.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Archer Pharmaceuticals - Targeted Drug Discovery

Archer Pharmaceuticals - Targeted Drug Discovery | Alzheimer's Disease R&D Review | Scoop.it

Archer Pharmaceuticals is devoted to finding cures for neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer's disease.


RC029 (Nilvadipine) is Archer’s first compound to be selected for clinical development. With Archer’s worldwide rights to ARC029 for its use in Alzheimer’s disease, it is our intention to fast track its development to deliver a first-in-class drug. 


ARC029 was selected from approximately 2,000 chemicals in the same class as our first-line treatment of Alzheimer’s for several reasons: The compound was one of the most proficient at lowering amyloid levels in the pre-clinical tests and models of Alzheimer’s disease. Very importantly ARC029 easily crosses the blood brain barrier, and there is evidence that it accumulates in the brain, which is important for targeting Alzheimer’s disease. Other drugs in the class do not cross the blood brain barrier. Importantly, ARC029 acts to lower the soluble forms of amyloid before they become deposits in the brain. We believe that the soluble forms (rather than the deposited forms) are the real culprit in the disease, and so reducing them is our goal with ARC029.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Alzheimer's drug developers still hoping for a homer

Alzheimer's drug developers still hoping for a homer | Alzheimer's Disease R&D Review | Scoop.it


BioPharma


Beta amyloid became a favorite drug target because plaques made of this protein are such a conspicuous finding in AD patients’ brains. Further, inherited and early-onset forms of AD are associated with mutations in the beta amyloid precursor protein (APP), reinforcing the hypothesis. However, several drugs that reduced the level of amyloid plaque in patients’ brains did little or nothing to slow the progress of the disease.


Some experts think the solution is to target the disease earlier. As a result, companies including Roche's Genentech, Biogen and Lilly, are focusing on studies in "mild-to-moderate" AD patients or even earlier. Others, such as Novartis, are looking at some patients who have no symptoms at all, but are at high risk of the disease. 


 Archer Therapeutics’ ARC029, meanwhile, specifically targets soluble forms of beta amyloid. Clearing these precursors from the brain, they hope, will prevent the plaques from forming at all.

more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease

Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease | Alzheimer's Disease R&D Review | Scoop.it
Highlights • The diagnostic accuracy of NFL protein in cerebrospinal fluid is examined. • A biomarker-based descriptive stratification model for AD is used. • NFL protein discriminates AD pathophysiology from HCs with fair diagnostic accuracy. • The ability of NFL protein in differentiating tau-positive patients from HCs is poor. • The ability of NFL in distinguishing AD pathophysiology from FTD is unsatisfactory.
Krishan Maggon 's insight:
Neurochemistry International Volume 108, September 2017, Pages 355-360
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Hypothalamic Stem Cells Could Provide New Insights Into Aging

Hypothalamic Stem Cells Could Provide New Insights Into Aging | Alzheimer's Disease R&D Review | Scoop.it
Treatments that limit inflammation in the region of the brain called the hypothalamus might be the key to slowing the aging process.
more...
No comment yet.
Scooped by Krishan Maggon
Scoop.it!

Drug Reverses Memory Failure Caused by Traumatic Brain Injury

Drug Reverses Memory Failure Caused by Traumatic Brain Injury | Alzheimer's Disease R&D Review | Scoop.it
UCSF scientists used an experimental drug to completely reverse severe learning and memory impairments caused by traumatic brain injury in mice.
more...
No comment yet.