Alzheimer’s Disease Without Amyloid Plaques

in medicine, biology

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease.  Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.  The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

Their results also indicate that by reducing the amount of APP within neurons it may be possible to rescue them.

The research report by Dr Belluscio and colleagues at the National Institute of Neurological Disorders and Stroke, Bethesda was published this week in The Journal of Neuroscience.
Alzheimer’s disease is a devastating brain disease that primarily affects the elderly and currently has no cure. It is characterized by a progressive loss of brain function leading to memory loss, dementia and eventual death. There are currently about 18 million people worldwide with Alzheimer’s disease and this figure is projected to nearly double by 2025. APP has long been linked to the neural loss in Alzheimer's disease, but its association to dying neurons has been difficult to capture in animal models, and how it causes neuron loss also remains unclear. Their  data suggest that excess production of APP alone within neurons can cause cell death, and that this process may be reversed when the amount of this toxic protein is reduced. 

Alzheimers disease without amyloid plaque
Image of nasal epithelium from a mutant mouse – showing mature olfactory sensory neurons expressing mutant-APP (Green), with many of them also expressing cleaved-Caspase 3 (Red), which is a marker of dying neurons. Image provided to by Dr.Leonardo Belluscio.

“To help us understand APP’s involvement in effecting neuron loss we utilized the unique attributes of the mammalian olfactory system,”  said Dr Belluscio and colleagues. The olfactory system is the part of the brain that allows us to perceive and interpret smells while maintaining an extraordinary capacity to regenerate. The specialized olfactory sensory neurons in the nose detect odor molecules in the air and send the information to the brain via direct axonal connections. Notably, smell dysfunction occurs early in Alzheimer’s disease, suggesting that the olfactory system may be more sensitive to the causal factors of the disease than other brain regions and thus could provide a sensitive platform to study these factors.

Using a transgenic approach the researchers developed a mouse model, in which high levels of a mutated APP, linked to familial forms of Alzheimer’s disease, was expressed in olfactory sensory neurons. They found that despite the absence of amyloid deposits in the extracellular space, a striking number of dying neurons were detected by three weeks of age. Importantly, this death occurred much earlier than that in other mouse models and was restricted to the neurons that produced the APP, sparing those residing side by side that did not make the protein. These results demonstrate that APP can induce neural death from inside the cells, challenging the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease. “Interestingly, we showed that by reducing the amount of APP using a genetic switch built into our system, the widespread neuron loss could be reversed, suggesting that such disease-related neural death might potentially be rescued,” they said.

“Our model mimics the olfactory sensory neuron loss reported in Alzheimer’s disease patients and suggests that the neurodegenerative process in the olfactory system may be similar to that in other brain regions,” said Dr Belluscio and colleagues. Because this model is based upon a primary sensory system, the sense of smell, it also offers a broad platform to examine the relationship between neuron death and other lifestyle factors, such as stress, diet and exercise which may also affect disease development. In addition, since the nose is a direct portal to the brain it offers easy access to tissues for both diagnostic purposes and for delivery of future therapeutic agents. “We feel this model will prove valuable not only for dissecting the pathological process of Alzheimer’s disease, but also for developing and testing new treatments,” they said. Deficits in odor detection and discrimination are among the earliest symptoms of Alzheimer’s disease, and thus can potentially serve as a “canary in the coal mine” for early diagnosis of this disorder.

Source Article: In Vivo Olfactory Model of APP-Induced Neurodegeneration Reveals a Reversible Cell-Autonomous Function. Ning Cheng, Huaibin Cai and Leonardo Belluscio. The Journal of Neuroscience, Published 28 September 2011, 31(39): 13699-13704; DOI: 10.1523/JNEUROSCI.1714-11.2011.

Additional Source: Dr. Leonardo Belluscio

Leonardo Belluscio Laboratory

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