Neurodegenerative Diseases

Neurodegenerative Diseases

Project 1: New BBB penetrable and neuron targeting nanotherapeutics for Azheimer’s Disease therapy

Introduction:

Alzheimer’s Disease (AD) is clinically characterized by a progressive decline in cognition and histologically by the presence in the brain Amyloid plaques (amyloid β, Aβ) which generated by the sequential cleavage of the amyloid precursor protein (APP) by BACE1 (β secretase) and γ-secretase. Given that BACE-1 plays a central role in cleaving APP to form neurotoxic Aβ. BACE-1 inhibition has emerged as an active focus area for new AD therapeutics. However, several challenges have retarded the development of BACE1 inhibitors, one of which is passing the blood-brain-barrier. Another challenge has been getting the degree of BACE-1 inhibition right. To address these challenges, we have successfully developed robust BBB penetrable and neuron targeting nanotherapeutics (glucose functionalized siRNA nanoparticles, GLU-NPs). GLU-NPs are able to effectively deliver BACE1 siRNA across BBB into brain, leading to effective gene knockdown for BACE1 in normal mice. This new BBB-penetrable nanotherapeutic represents an exciting advance for siRNA delivery into the brain and may hold great potential as a new AD treatment.

Hypotheses: GLU-NPs can selectively deliver BACE1 siRNA into neurons as nanotherapeutics via the glucose transporter pathway and efficiently down-regulate the expression of BACE1 mRNA reducing amyloid burdens, respectively, with improvements in cognitive behaviour in amyloid AD transgenic mouse models.

Aim 1: To characterise the mechanism of neuronal targeting by GLU-NPs in vitro and in the brain.

Aim 2:To establish effective and safe dose schedules for GLU-NPs containing BACE1 siRNA for administration in an AD transgenic mouse model.

Aim 3:To define the effectiveness of GLU-NPs containing based BACE1 siRNA to reduce amyloid deposition and improve cognitive performance in APP23 AD mice.

Outcomes: We expect that we can figure out the precise mechanism that our GLU-NPs use to permeate the BBB and to specifically target neurons. The research results can convince us that our siRNA-loaded GLU-NPs could be a potential new therapy for AD.

Enquires:Professor Roger Chung, roger.chung@mq.edu.au

Dr Marco Morsch, marco.morsch@mq.edu.au

Dr Albert Lee, albert.lee@mq.edu.au

Dr Bingyang Shi, bingyang.shi@mq.edu.au

Project 2:  Investigate blood protein alterations in autosomal dominant Alzheimer’s disease

Introduction: There is still no definitive pre-mortem diagnosis for Alzheimer’s disease (AD) and the current gold standard markers are either invasive or expensive for population wide screening. The advertised Ph.D. position will investigate proteomic alterations in the blood to identify potential blood biomarkers for the early diagnosis of AD, in a unique cohort that comprises adult offspring of biological parents carrying a mutation responsible for autosomal dominant Alzheimer’s disease (ADAD), wherein individuals carrying the ADAD mutation are predestined to AD.

Hypothesis: AD pathogenesis-related blood biochemical changes can identify pre-clinical Alzheimer’s disease

Aims: Investigate blood proteomic alterations between ADAD mutation carriers and non carriers, and validate findings in an independent sporadic AD cohort.

Method: Blood proteomic profiles will be examined using state of the art proteomic platforms employing mass spectrometry and enzyme linked immunosorbent assays.

Enquires:
Professor Ralph Martins

Email: ralph.martins@mq.edu.au

Project 3: Investigate blood protein alterations in preclinical Alzheimer’s disease

Introduction: There is still no definitive pre-mortem diagnosis for Alzheimer’s disease (AD) and the current gold standard markers are either invasive or expensive for population wide screening. The advertised Ph.D. position will investigate proteomic alterations in the blood to identify potential blood biomarkers for the early diagnosis of AD in a highly-characterised cohort, wherein approximately 30% of study participants are in the preclinical stage of AD, as assessed from the brain beta amyloid load, a gold standard marker of AD.

Hypothesis: AD pathogenesis-related blood biochemical changes can identify pre-clinical Alzheimer’s disease.

Aims: Investigate blood proteomic alterations between individuals in the preclinical phase of AD versus healthy control individuals, and validate findings in an independent cohort.

Methods: Blood proteomic profiles will be examined using state of the art proteomic platforms employing mass spectrometry and enzyme linked immunosorbent assays.

Enquires:
Professor Ralph Martins

Email: ralph.martins@mq.edu.au

Project 4: Machado Joseph disease research using transgenic zebrafish and mice

Introduction

Machado Joseph disease (also known as spinocerebellar ataxia-3) is a fatal neurodegenerative disease that causes impaired balance and movement control, leading to paralysis and death. It is known that the disease is caused by inheritance of an abnormal form of the ataxin-3 gene, containing a long CAG-repeat region. The Machado Joseph disease research group, lead by Dr. Angela Laird, has developed a transgenic zebrafish model of the human disease that develops signs of the human disease such as impaired swimming behaviour. We are testing the effect of treatment with a range of potential disease treatments on these zebrafish, including drugs hypothesised to induce the quality control pathways autophagy and the proteasome. Drugs that are found to be protective in the MJD zebrafish will also need to be tested on other models of MJD such as cell cultures and a MJD mouse model, to confirm whether they may be useful for use in MJD patients.

Aims:

  1. Test for drugs and small compounds that have protective effects on transgenic MJD zebrafish
  2. Confirm whether treatment with protective drugs identified above, and within our previous studies, are also protective in other MJD models (cell cultures and mouse model)

Research Plan:

The effect of treatment with different drugs and small compounds will be tested on our transgenic MJD zebrafish. We will observe whether any treatments can prevent development of impaired swimming behaviours, or decrease the amount of the aberrant form of human ataxin-3 protein, within the MJD zebrafish. Treatments that are found to be effective will be explored further within our MJD zebrafish studies and cell culture studies. Treatments that warrant further investigation will also be tested on a MJD mouse model and the effect on motor behaviour, development of neuropathology and survival.

Enquires:

Dr. Angela Laird, angela.laird@mq.edu.au

Project 5: Investigate the diagnostic utility of hyperspectral retinal imaging in preclinical Alzheimer’s disease

Introduction

There is still no definitive pre-mortem diagnosis for Alzheimer’s disease (AD) and the current gold standard markers are either invasive or expensive for population wide screening. The advertised Ph.D. position will investigate changes occurring in the retina in the eyes of study participants using a breakthrough NASA inspired technology and its relationship with changes occurring in the brain. This will enable us to identify potential biomarkers in the eye for the early diagnosis of AD in a highly-characterized cohort, wherein approximately 30% of study participants are in the preclinical stage of AD, as assessed from the brain beta amyloid load, a gold standard marker of AD.

Hypothesis

AD pathogenesis-related biomarkers in the retina can identify pre-clinical Alzheimer’s disease.

Aims

Identify retinal biomarkers, spectral and textural patterns in the eyes of individuals in the preclinical phase of AD versus healthy control individuals, and validate findings in an independent cohort.

Methods

Hyperspectral retinal imaging will be performed using state of the art metabolic hyperspectral retinal camera (MHRC) along with other cognitive and retinal assessments, blood biomarker analysis and brain imaging. The MHRC has been purchased by the Macquarie University for this project and is one of the only 3 currently available in Australia (the second camera is at our Perth site).

Enquiries

Professor Ralph Martins Email: ralph.martins@mq.edu.au

Dr Tejal Shah Email: tejal.shah@mq.edu.au

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