Beta-Amyloid, Tau Proteins & Therapeutic Ultrasound – Alzheimer’s Disease

Alzheimer’s disease is marked by cognitive and social deficits that can vastly affect quality of life. Despite the relatively high prevalence of the disease and our growing understanding of its pathology, we have yet to develop effects preventions and treatments for the disease. Though many attempts to intervene in the disease have involved pharmaceuticals, in the past couple of years, researchers have been targeting beta-amyloid and tau proteins with new types of technologies to tackle the problem of Alzheimer’s disease.

Alzheimer’s Disease

Alzheimer’s disease is characterized by memory loss but also has other devastating symptoms, including difficulty with planning and decision making. Confusion with respect to both time and location are prominent features of the disease. Though the disease is often considered one that adversely impacts cognitive abilities, its effects on judgment also bring with it significant social consequences that can alter behavior and harm relationships. [1]

Anxiety, depression, and paranoia are common in Alzheimer’s disease, and though there are medications to treat these symptoms, interventions that fix their underlying causes have long evaded scientific researchers. There is no effective prevention, vaccine, or cure for Alzheimer’s disease. Recently, scientists have begun employing novel methods for dealing with Alzheimer’s disease that stray from more traditional pharmaceutical approaches.

Two examples are groups at the University of Queensland and the University of Southern California who are leveraging the body’s immune system to destroy toxic substances in the brain that lead to Alzheimer’s disease. Other scientists are continuing to pursue pharmacological treatments and creating novel ways to test drugs with greater efficiency.

Beta-Amyloid | PET brain scans of healthy, cognitively normal patients. PET brain scans of patients with symptoms of mild Alzheimer’s disease. (Credit: Mathieu Brier. Washington University)
Beta-Amyloid | The Beta-Amyloid protein is a hallmark of Alzheimer's Disease (Credit: Leonard Lessin. Science)

Left: PET brain scans of healthy, cognitively normal patients (top) vs PET brain scans of patients with symptoms of mild Alzheimer’s disease (bottom). Right: The Beta-Amyloid protein is a hallmark of Alzheimer’s Disease.

Left: PET brain scans of healthy, cognitively normal patients (top) vs PET brain scans of patients with symptoms of mild Alzheimer’s disease (bottom). Right: The Beta-Amyloid protein is a hallmark of Alzheimer’s Disease.

Top: PET brain scans of healthy, cognitively normal patients vs PET brain scans of patients with symptoms of mild Alzheimer’s disease. Bottom: The Beta-Amyloid protein is a hallmark of Alzheimer’s Disease.

Top: PET brain scans of healthy, cognitively normal patients vs PET brain scans of patients with symptoms of mild Alzheimer’s disease. Bottom: The Beta-Amyloid protein is a hallmark of Alzheimer’s Disease.

Beta-Amyloid, Tau Proteins vs. Therapeutic Ultrasound

A group at the Queensland Brain Institute is employing a form of ultrasound, termed therapeutic ultrasound, to create sound waves in the brain that can breakup the problematic proteins associated with Alzheimer’s disease. Of particular significance is that the technology impacts these proteins – beta-amyloid and tau – non-invasively, making the technique relatively painless and easy. According to the scientists using this method, the effectiveness of the sound wave technology lies in its ability to impact the blood-brain barrier. [2]

This barrier normally prevents substances from entering the brain, but with sound waves that can temporarily open this barrier, the researchers claim that microglia, which are immune system components of the brain, are activated. This activation enables microglia to remove toxic materials from the brain. Gaining this special access to the destructive proteins associated with Alzheimer’s disease may prove a promising way to rid the brain of physiological hallmarks of the disease and restore normal functioning in those with the disease. [3]

It may also potentially be used to prevent the accumulation of these proteins and the initial development of the disease in those at risk. The results of some studies that have been shown to impact beta-amyloid and tau proteins in the brain have been diminished by a lack of association with changes in symptoms of dementia. However, therapeutic ultrasound has been shown to improve memory function in the majority of mice in which it has been tested.

More specifically, about 75% of mice that underwent therapeutic ultrasound improved their performance in object and place recognition tasks as well as in navigating mazes. Thus, the impact of therapeutic ultrasound not only altered brain physiology in models of Alzheimer’s disease but also restored normal brain functioning in these mice. Thanks to these promising results, the group will move on to trials in other animal models and aim to start human trials in 2017. [4]

RN2N treatment in combination with SUS reduces anxiety-like behaviour in pR5 tau transgenic mice.


Beta-Amyloid | RN2N treatment in combination with SUS reduces anxiety-like behaviour in pR5 tau transgenic mice: (A) Schematic of ultrasound treatment using a transducer in scanning (SUS) mode in order to achieve microbubble-assisted opening of the blood–brain barrier. (B) Female pR5 mice at 4.5 months of age were randomly assigned to one of four groups: pR5, pR5 + SUS, pR5 + RN2N and pR5 + RN2N + SUS and treated as indicated (X) once a week for 4 weeks. A group of wild-type (WT) littermate controls did not undergo any treatment. Upon treatment completion, mice were analysed on the elevated plus maze (EPM), and then sacrificed.

(A) Schematic of ultrasound treatment using a transducer in scanning (SUS) mode in order to achieve microbubble-assisted opening of the blood–brain barrier.

(B) Female pR5 mice at 4.5 months of age were randomly assigned to one of four groups: pR5, pR5 + SUS, pR5 + RN2N and pR5 + RN2N + SUS and treated as indicated (X) once a week for 4 weeks. A group of wild-type (WT) littermate controls did not undergo any treatment. Upon treatment completion, mice were analysed on the elevated plus maze (EPM), and then sacrificed.


Beta-Amyloid | RN2N treatment in combination with SUS reduces anxiety-like behaviour in pR5 tau transgenic mice: (C) The elevated plus maze is an elevated crossshaped apparatus with a central square and 15 cm long x 5 cm wide closed arms with a 15 cm wall and open arms with unprotected edges. (D) The mean positional heat map within the elevated plus maze for each treatment group.

(C) The elevated plus maze is an elevated crossshaped apparatus with a central square and 15 cm long x 5 cm wide closed arms with a 15 cm wall and open arms with unprotected edges.

(D) The mean positional heat map within the elevated plus maze for each treatment group.


Beta-Amyloid | RN2N treatment in combination with SUS reduces anxiety-like behaviour in pR5 tau transgenic mice: (E) pR5 mice (n = 6) spend significantly less time in the open arms compared to wild-type mice (n = 7) (****P50.0001). No difference was observed in the pR5 + SUS group (n = 6) compared to the pR5 mice. However, mice in the pR5 + RN2N group (n = 6) and those in the pR5 + RN2N + SUS group (n = 5) spent significantly more time in the open arms than pR5 mice (*P = 0.03 and ***P = 0.0002, respectively), indicating a reduction in anxiety-like behaviour (mean ‡ SEM; one-way ANOVA with Dunnett’s multiple comparison test).

(E) pR5 mice (n = 6) spend significantly less time in the open arms compared to wild-type mice (n = 7) (****P50.0001). No difference was observed in the pR5 + SUS group (n = 6) compared to the pR5 mice. However, mice in the pR5 + RN2N group (n = 6) and those in the pR5 + RN2N + SUS group (n = 5) spent significantly more time in the open arms than pR5 mice (*P = 0.03 and ***P = 0.0002, respectively), indicating a reduction in anxiety-like behaviour (mean ‡ SEM; one-way ANOVA with Dunnett’s multiple comparison test).

Leveraging The Body’s Immune System

A separate group of scientists, located at the University of Southern California’s Keck School of Medicine recently published findings that, similar to the Queensland group, leverages the body’s immune system to clear toxins from the brain. Their results, published in the journal Neuron, showed that when a substance, interleukin-10, was blocked in mice, beta-amyloid plaques in the brain were destroyed. As with therapeutic ultrasound, this technique was also associated with behavioral change, restoring memory function in mice. [5] [6]

Effects of Diet and Fasting on Alzheimer’s

In addition to outside-the-box approaches to therapy for Alzheimer’s disease, scientists are also finding novel, innovative ways to study the of effects diet and certain drugs on the disease. For instance, fasting has been shown to slow the progression of Alzheimer’s in mice by reducing circulating IGF-1 levels. Similar studies have shown that drastically cutting calorie intake may help protect against the damage caused by neurodegenerative disorders such as Alzheimer’s and Parkinson’s. [7] [8]

Using Basal Forebrain Cholinergic Neurons to Test Drugs

Scientists at Northwestern in Chicago have created basal forebrain cholinergic neurons, whose death early in Alzheimer’s disease is associated with memory loss. The researchers are using these cells, made from human embryonic stem cells, to test the impact of drugs on this particular type of neuron. This strategy can vastly improve the efficiency with which we can test the potential of Alzheimer drug candidates and could increase our chances of identifying an effective treatment for this devastating disease. [9] [10]

The formation of beta-amyloid (Aβ) peptide, eventually aggregates into soluble Aβ oligomer and insoluble Aβ peptide plaque. Aβ is crucial in the formation of senile plaques in AD.


Beta-Amyloid | The formation of beta-amyloid (Aβ) peptide, eventually aggregates into soluble Aβ oligomer and insoluble Aβ peptide plaque: (A) Various environments of the brain, such as plasma membrane, trans-Golgi network, endoplasmic reticulum and endosomal, lysosomal and mitochondrial membranes, feature (among others) a cell interior, a cell membrane and an APP (amyloid precursor protein) molecule.

Various environments of the brain, such as plasma membrane, trans-Golgi network, endoplasmic reticulum and endosomal, lysosomal and mitochondrial membranes, feature (among others) a cell interior, a cell membrane and an APP (amyloid precursor protein) molecule.


Beta-Amyloid | The formation of beta-amyloid (Aβ) peptide, eventually aggregates into soluble Aβ oligomer and insoluble Aβ peptide plaque: (B) The enzyme induced cleavage of the parental amyloid precursor protein (APP) creates various fragments of protein including the beta-amyloid (Aβ) peptide. A beta-amyloid peptide is a 39–43 amino acids long peptide that can exist in multiple assembly states: monomers (peptides), oligomers, protofibrils and fibrils.

The enzyme induced cleavage of the parental amyloid precursor protein (APP) creates various fragments of protein including the beta-amyloid (Aβ) peptide. A beta-amyloid peptide is a 39–43 amino acids long peptide that can exist in multiple assembly states: monomers (peptides), oligomers, protofibrils and fibrils.


Beta-Amyloid | The formation of beta-amyloid (Aβ) peptide, eventually aggregates into soluble Aβ oligomer and insoluble Aβ peptide plaque: (C) Aβ peptides spontaneously aggregate into fibrils, which eventually lead to the formation of insoluble Aβ plaques. Additionally, soluble Aβ oligomers are found to be toxic since they can bind to different neurotransmitter receptors and thus stimulate kinase dysfunction, oxidative stress, and synapse loss. Both insoluble Aβ plaques and soluble Aβ oligomers lead to the loss of neurons.

Aβ peptides spontaneously aggregate into fibrils, which eventually lead to the formation of insoluble Aβ plaques. Additionally, soluble Aβ oligomers are found to be toxic since they can bind to different neurotransmitter receptors and thus stimulate kinase dysfunction, oxidative stress, and synapse loss. Both insoluble Aβ plaques and soluble Aβ oligomers lead to the loss of neurons.

Image Credit

Nisha Kaul Cooch is Founder and Principal of BioInnovation Consulting LLC, a life sciences communications firm based in Washington DC. While earning her Ph.D. in Neuroscience, she studied the nature of decision making and information processing. The focus of her current work is entrepreneurship in the biotechnology industry.

Nisha Kaul Cooch is Founder and Principal of BioInnovation Consulting LLC, a life sciences communications firm based in Washington DC. While earning her Ph.D. in Neuroscience, she studied the nature of decision making and information processing. The focus of her current work is entrepreneurship in the biotechnology industry.

Nisha Kaul Cooch is Founder and Principal of BioInnovation Consulting LLC, a life sciences communications firm based in Washington DC. While earning her Ph.D. in Neuroscience, she studied the nature of decision making and information processing. The focus of her current work is entrepreneurship in the biotechnology industry.

Nisha Kaul Cooch is Founder and Principal of BioInnovation Consulting LLC, a life sciences communications firm based in Washington DC. While earning her Ph.D. in Neuroscience, she studied the nature of decision making and information processing. The focus of her current work is entrepreneurship in the biotechnology industry.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.