Page 18 - SFRBMdot July 2015

Scanning ultrasound removes amyloid-β and restores memory in an Two-pore channels control Ebola virus host cell entry and are drug

Alzheimer’s disease mouse model. Leinenga G and Götz J, Sci. Transl. targets for disease treatment. Sakurai Y, Kolokoltsov A, Chen C-C, Tidwell

Med. 11, 278ra33 (2015). DOI: 10.1126/scitranslmed.aaa2512
M, Bauta W, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey R.

Science, Feb 27; 134(6225), 2015.
The chronic neurodegenerative Alzheimer’s disease is the most common

type of dementia which can lead to confusion, loss of memory and ability Ebola virus (EBOV), the constituent of the family Filoviridae, causes a highly

to care for oneself and even speak. Thus far no cure is available. Amyloid-α lethal, rapid progressing hemorrhagic fever in humans and nonhuman

peptide has been implicated in the pathogenesis of Alzheimer’s disease primates. However, no drug treatment or broadly active vaccine exists

by aggregating into extracellular ibrillar deposits known as amyloid yet. With the goal of inding therapeutic target(s) for disease treatment,

plaques. This study extends and veriies earlier indings from a group the authors investigated the functional mechanism of EBOV infection.

from University of Toronto (Radiology 2014, DOI: 10.1148/radio.14140245). The researchers performed several experiments and based on reported

Thus, Götz and Leinenga of the University of Queensland, Australia, have studies they discovered the speciic mechanism of Ebola virus entry into

demonstrated that bombarding mouse brains with ultrasound waves the host cell. EBOV enters the host cell by macropinocytosis following

not only removed disease-related amyloid-α plaques, but also restored an endosomal pathway. Further calcium host proteins are important for

the memory in mice with Alzheimer’s-like symptoms. The authors used Ebola virus host cell entry. When combined with a series of studies that

repeated scanning ultrasound, which allows for a transient opening have explored the ability of known drugs to block the infection, as well

of the blood-brain barrier, as a non-pharmacological approach for as using the gene knockout, small interfering RNA, or small molecule

removing amyloid-α plaques and restoring memory function in a mouse inhibitors to disrupt the function of the two-pore channel (TPC), the

model. Genetically engineered mice that spontaneously produce authors were able to show that the TPC, the main calcium channels

brain amyloid-α plaques and exhibit memory deicits were used. After activated by nicotinic acid adenine dinucleotide phosphate (NAADP),

ive treatments during a period of six weeks, a 56% reduction in brain are responsible for controlling the movement of the virus-containing

area containing amyloid-α plaques relative to untreated animals was endosomes. Consequently, the authors show that TPCs may be effective

found. Spinning disk confocal microscopy and high-resolution three- targets for anti-EBOV. They have tested this possibility via using the

dimensional reconstruction revealed extensive internalization of existing drugs. They showed that the tetrandrine is the most effective

amyloid-α peptide into the lysosomes of activated microglia in mouse drug. They further showed that it has therapeutic eficacy in mice

brains subjected to scanning ultrasound treatment, with no concomitant infected with Ebola viruses. They suggest this may be due to its ability

increase in microglial cells number. Analysis of nuclear factor αB and glial to block both the TPC1 as TPC2, which are responsible for controlling

ibrillary acidic protein suggested that scanning ultrasound treatment different stages of endosomal traficking. By disrupting TPC function,

did cause inlammation. Furthermore, the ultrasound-exposed mice EBOV is prevented from escaping the endosomal network into the cell

showed improved performance relative to unexposed animals in three cytoplasm, halting infection. They also explored the possibility that this

independent memory-related behavior tests: Y-maze, the novel object drug may control the infection of other iloviruses such as Marbugvirus,

recognition test and the active place avoidance task. Further work is further supporting the notion that this family of viruses requires TPC

needed to provide evidence that ultrasound methodology does not function to infect host cells. (Reviewed by Jacqueline Cristina Bueno-

cause additional damage to already compromised blood-brain barrier Janice and Ines Batinic-Haberle, Duke University School of Medicine).

of Alzheimer’s patients (Reviewed by Romulo Severo Sampaio and Ines

Batinic-Haberle, Duke University School of Medicine).

SFRBM Newsletter // July 2015 // Literature Review

1 8 IN THIS ISSUE V I S I T U S O N L I N E : W W W . S F R B M . O R G