Nav: Home

Therapeutic strategies targeting Alzheimer's disease-related molecules

August 05, 2016

Therapeutic strategies targeting Alzheimer's disease (AD)-related molecule β-amyloid (Aβ), Tau protein and BACE enzyme have been recently explored. However?the therapeutic efficacy for a single target is not ideal. The clinical trials that clean Aβ from the brain in AD patients were largely unsuccessful. It is well known that the inflammatory response is one component of AD pathogenesis, leading to a series of irreversible pathological events. Epidemiological evidences show that long-term use of non-steroidal anti-inflammatory drugs has a sparing role in AD, but it failed to prevent the progression of symptoms in AD patients in randomized clinical trials. Possible reasons for the failure of anti-inflammatory drugs may be associated with: 1) the advanced state of disease or the dosing regimens of drugs; 2) most of the available anti-inflammatory drugs are not really "anti-inflammatory"; 3) these "anti-inflammatory" drugs only prevent the pro-inflammatory responses, but do not trigger the anti-inflammatory responses.

Fasudil, a selective Rho kinase (ROCK) inhibitor, may be a more appropriate therapeutic option in the treatment of patients with AD. Our previous studies provided many evidence that Fasudil inhibited the inflammatory response in both experimental autoimmune encephalomyelitis (EAE) and Parkinson's disease (PD) models through converting inflammatory M1 microglia/macrophage to anti-inflammatory M2 cells. The investigations from other groups also demonstrated therapeutic potential in EAE, PD and amyotrophic lateral sclerosis (ALS). It should be noted that the inhibition of inflammatory microglia is essential for the neuroprotective effects of ROK inhibitor on MPTP-induced dopaminergic cell death. Based on these reasons, we designed the study to observe therapeutic potential of Fasudil, and explored possible mechanisms in APP/PS1 transgenic mice.

Our results show that administration of Fasudil improved learning and memory deficits in APP/PS1 Tg mice. The expression of Aβ1-42 in hippocampus and brain of mice was clearly observed in APP/PS1 Tg mice, while treatment of Fasudil reduced the expression of Aβ1-42 in hippocampus of APP/PS1 mice. Tau protein intracellular neurofibrillary tangles (NFTs) pathology is the major correlation between clinical symptoms and main feature in AD. Tau-induced animal models reproduce neuronal and glial Tau pathology, leading to the progressive cognitive and/or motor impairment and premature death. Our results demonstrated that the treatment of Fasudil decreased the number of p-Tau/Ser396-positive cells and expression of p-Tau/Ser396 protein in brain of APP/PS1 Tg mice. BACE is a β-site APP cleaving enzymes that is a major drug target for AD because of BACE-mediated cleavage of APP and decrease of Aβ. To investigate whether Fasudil intervention influences the levels of BACE, we observed the expression of BACE in the hippocampus and brain. The expression of BACE protein in brain of App/PS1+saline mice was elevated significantly compared with those of wild-type mice and were dramatically downregulated upon treatment with Fasudil for 8 weeks. PSD-95 is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory that is regulated by Aβ. The treatment of Fasudil increased the expression of PSD-95 in App/PS1 mice. Taken together, Fasudil ameliorated learning and memory deficits, accompanied by reduced Aβ deposition, Tau phosphorylation, BACE expression, as well as increased PSD-95 expression in hippocampus.

It has become increasingly apparent that neuroinflammation plays an important role in the pathology of AD. Our results found that the treatment of Fasudil also inhibited TLR-2/4, MyD88, p-NF-κB/p65, IL-1β, IL-6 and TNF-α, and induced IL-10 in App/PS1 mice.

AD is a complex aging-related disease caused by a variety of genetic and environmental factors. Currently therapeutic agents approved by the US Food and Drug Administration (FDA), including donepezil, rivastigmine, galantamine and memantine, are unable to prevent or reverse disease progression and are only modestly efficacious. A series of irreversible pathological events coexist in the pathogenesis of AD, including inflammatory response, toxic to neurons, oxidative stress, activated microglia and loss of Aβ clearance ability. The novel therapeutic strategy should target multiple aspects of AD, e.g., attenuates the Aβ burden and Tau phosphorylation, and/or converts beneficial microglia polarization. Fasudil exhibited a multitarget therapeutic effect in APP/PS1 transgenic mice by the reduction of Aβ deposition and Tau phosphorylation, the decrease of BACE and the increase of PSD-95, as well as inhibition of TLRS-NF-κB-MyD88 inflammatory axis. However, these results still need to be repeated and confirmed before clinical application.
Reference: Yu, J.-Z.; et al. (2016). Multitarget therapeutic effect of Fasudil in APP/PS1transgenic mice, CNS Neurol. Disord. Drug Targets., DOI: 10.2174/1871527315666160711104719

Bentham Science Publishers

Related Brain Articles:

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.
Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.
Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.
Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.
BRAIN Initiative tool may transform how scientists study brain structure and function
Researchers have developed a high-tech support system that can keep a large mammalian brain from rapidly decomposing in the hours after death, enabling study of certain molecular and cellular functions.
Wiring diagram of the brain provides a clearer picture of brain scan data
In a study published today in the journal BRAIN, neuroscientists led by Michael D.
Blue Brain Project releases first-ever digital 3D brain cell atlas
The Blue Brain Cell Atlas is like ''going from hand-drawn maps to Google Earth'' -- providing previously unavailable information on major cell types, numbers and positions in all 737 brain regions.
Landmark study reveals no benefit to costly and risky brain cooling after brain injury
A landmark study, led by Monash University researchers, has definitively found that the practice of cooling the body and brain in patients who have recently received a severe traumatic brain injury, has no impact on the patient's long-term outcome.
Brain cells called astrocytes have unexpected role in brain 'plasticity'
Researchers from the Salk Institute have shown that astrocytes -- long-overlooked supportive cells in the brain -- help to enable the brain's plasticity, a new role for astrocytes that was not previously known.
Largest brain study of 62,454 scans identifies drivers of brain aging
In the largest known brain imaging study, scientists from Amen Clinics (Costa Mesa, CA), Google, John's Hopkins University, University of California, Los Angeles and the University of California, San Francisco evaluated 62,454 brain SPECT (single photon emission computed tomography) scans of more than 30,000 individuals from 9 months old to 105 years of age to investigate factors that accelerate brain aging.
More Brain News and Brain Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab