Researchers Develop 'Early Warning' Probe for Alzheimer's Disease – Advance May Lead To A Cure

Researchers at Northwestern University have developed a hybrid nanoparticle-antibody probe that functions as an “early warning system” for detecting Alzheimer’s Disease (AD).

Neuroscientist William Klein and nanotechnologist Vinayak Dravid combined an engineered  antibody (an immune molecule that binds strongly with an antigen or pathogenic molecule) with iron-oxide nanoparticles to create a probe that — in conjunction with MRI technology — was able to distinguish between healthy and diseased human brain samples.

It is well-established that an uncontrolled accumulation of beta-amyloid proteins into plaques represents the hallmark of AD and its progression throughout the brain. Most neuroscientist agree that a smaller, particulate, form of the protein — called an oligomer* — is the primary pathogenic agent of the memory-destroying disease. These toxic oligomers clump together to form the characteristic plaques associated with the onset of AD. At that stage, the disease has already progressed, and so, the goal is to predict disease risk prior to this advanced oligomerization stage.

The antibody-nanoparticle probe is able to detect and bind to these oligomer toxins, and, due to the magnetic potential of the iron-oxide nanoparticles, the location and volume of the oligomers are readily detected via magnetic resonance imaging (MRI) technology.

The earlier the detection, the sooner patients can start treatment. The new detection system permits earlier detection than was previously possible — so newly diagnosed AD patients can begin treatment earlier.

“Once the chain reaction of negative events starts, it’s like a lit fuse. You want to intervene as soon as possible,” Klein says. [source, see link below]

More Details, More Research

In initial clinical applications, the detection system would be used to verify how well a patient is responding to a new therapeutic medicine, but the researchers also foresee their system being used as a primary treatment to deliver anti-oligomer therapeutics (or to trigger a powerful immune response) to eradicate the brain-wasting plaques and/or possibly reverse the disease entirely.

Alzheimer dementia 'senile plaques'
Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer’s disease of pre-senile onset. Silver impregnation (image: userKOH).

The detection system described in the research was used on human brain samples — not actual living brains. The next step in this research is to test the the system on the brains of living animals (mice). Preliminary tests  have been successful in delivering the nanoparticles to a mouse’s brain via a nasal spray. This result alone is a significant proof of principle that such particles can effectively penetrate the blood-brain barrier (BBB) — an obstacle that has in the past hindered delivery of therapeutics directly to brain tissue.

It is believed that the same delivery technique will work with living humans; what remains is testing this technique with the combined antibody therapy, and, of course, determining how effective it is in detecting early stage AD, and, if utilized as a primary therapeutic, in controlling the spread of the oligomer plaques.

The use of iron-oxide nanoparticles in this system is deemed safe; if no oligomers are present (detected) in the brain, the iron-oxide particles pass safely out of the body.

However, there is evidence (Huang et al, 2004, M.A. Smith et al, 1997) for a link between abnormal concentrations of metal ions in the brain and the neurodegeneration associated with AD. Such redox-active metal ions (like ions of iron) can lead to a build up of radical oxygen species (ROS) causing oxidative damage to cells. So, the success of this technique as a treatment may partly depend on how quickly and thoroughly such metal nanoparticles pass out of one’s brain tissue.

The design of such therapeutic antibodies is typically the domain of the bioengineering industry working in conjunction with the pharmaceutical industry. This combining of bioengineered antibodies  with nanoparticle technology represents a fairly recent trend: the convergence of the biotech and nanotech industries.

This current research was published by Klein Lab News under the title: ‘Nanotechnology That Detects and Treats Alzheimer’s’.

While the beta-amyloid hypothesis of AD causation is the current, dominant theory, there are other hypotheses of AD etiology, such as the tau protein hypothesis (in which “hyperphosphorylated” tau-proteins combine to form the neurofibrillary tangles inside nerve cell bodies, causing the cells’ microtubule structures to disintegreate); also, some researchers have posited the Herpes simplex virus type 1 as a causative agent in those with a mutation in the apoE gene (Itzhaki RF, Wozniak MA, 2008). Further, some researchers, including Klein, are beginning to view AD as a form of diabetes (see note below).

* The soluble oligomers (comprising the Beta-amyloid proteins) are termed ADDLs, for amyloid-derived diffusible ligands. These ligands are spcialized proteins that bind to insulin receptors, damaging them, and interfering with insulin absorption. These ADDLs were discovered by Klein (2007), who has stated: “I think it’s likely that if you block ADDLs, you will be able to reverse or prevent Alzheimer’s…

Note that Beta-amyloid is itself a fragment from a larger protein called amyloid precursor protein (APP), which is a type of (neural) transmembrane protein.

Some General Facts About Alzheimer’s Disease:

Alzheimer’s disease is among the most common brain disorders affecting the elderly population the world over, and is projected to become a major health problem with grave socio-economic implications in the coming decades. The total number of people afflicted by Alzheimer’s disease (AD) worldwide today is about 15 million people, a number expected to grow by four times by 2050.

The pathogenesis of AD is characterized by loss of neurons and synapses, resulting in gross atrophy across multiple brain regions. The disease is presently hard to reliably diagnose, particularly in its early stages when it is often mistaken for more normal age-related or stress-related changes. While an accurate diagnosis can only be obtained post-mortem (via examination of brain tissue in an autopsy), current clinical methods involving brain imaging and neuropsychological testing are only about 85% accurate, and that too only at later stages.

[source: Fighting Alzheimer’s disease with nanotechnology]

Some additional source material for this post came from the SciAm aricle: ‘Scientists Develop Early-Warning System for Alzheimer’s Disease’ by Stephani Sutherland

Top Image: PET scan of the brain of a person with AD showing a loss of function in the temporal lobe (image source: NIA/NIH)


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