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Alternative Hypothesis of Neuronal Death in Alzheimer’s Disease
Unfortunately, many of the latest studies attempting to treat and possibly cure Alzheimer’s disease continue to lack efficacy. The amyloid deposition hypothesis, which has been tested in these failed studies, is based on the belief that amyloid beta, a protein, mysteriously accumulates in areas in the brain over time to form amyloid plaques. Eventually, these plaques are thought to kill nearby neurons, leading to the clinical symptoms observed in Alzheimer’s patients.
My evidence suggests that the basic pathology of Alzheimer’s does not begin outside of the neurons in the Alzheimer’s brain, but inside them. This amyloid, a typically useful protein in memory and made by neurons, begins to accumulate unnaturally in the brain through a vascular leak in the blood-brain barrier, which normally tightly regulates the passage of blood components into the brain. Over time, the amyloid pools at those areas of the vascular leaks and forms plaques. However, it is imperative to understand that these types of amyloid plaques, called diffuse plaques for their appearance, are harmless and not associated with cell death and inflammation.
This vascular-derived amyloid can also enter neurons through a receptor. Over time, susceptible neurons continue to accumulate toxic amounts of this amyloid to the point of degenerating. When these amyloid-laden neurons die, they release enzymes that indiscriminately digest local proteins, leaving indigestible material in their place as the so-called dense-cored amyloid plaque, also named for its appearance.
The death of each neuron is problematic in itself, but unfortunately the death also sets off a catastrophic chain of events. Each dead neuron releases once-regulated intracellular enzymes into the brain, which freely digest other neuron-sensitive proteins in the area. As you might imagine, the brain is densely filled with neuronal processes originating from hundreds of neurons. This means that the enzymes released from the dead neuron are free to digest all sensitive proteins in the area, potentially causing harm to all local neurons.
In addition, each dead neuron also triggers a reactive response from the local inflammatory cells (e.g. astrocytes, microglia) that try to heal the toxic area. Unfortunately, these brain-specific inflammatory cells also secrete signaling proteins that further damage nearby neurons.
In summary, neurons appear to be dying through several mechanisms that eventually lead to Alzheimer’s disease: some neurons are dying from the toxic accumulation of amyloid, while others are damaged by being on contact with the toxic area of the dead neuron, and others still are harmed by local inflammatory cells.
If this proposed pathology is accurate, cleaning up the brain with anti-amyloid antibodies is irrelevant and will never revive the dead neurons, unless the anti-amyloid antibodies inhibit the internalization of amyloid into these neurons. Therefore, two therapeutic approaches to consider curing AD begin with sustaining a functional blood-brain barrier to prohibit vascular-derived amyloid from entering the brain and inhibiting amyloid from entering the neurons.
In his newly released book Bursting Neurons and Fading Memories in Alzheimer’s Disease, Michael presents an alternative hypothesis describing the events leading to neuronal death.
If you are interested in further understanding of the details and evidence of this alternative approach, the book is available on the Elsevier Store. Use discount code “STC215″ at checkout and save up to 30% off the list price. He has also created a video in which he describes his “Inside-Out Hypothesis” below:
About the Book:
Advances in Alzheimer’s disease (AD) research have been challenging and without major breakthroughs in understanding its pathological basis. The reigning hypothesis suggests AD is the result of extracellular amyloid deposition that seed to form amyloid plaques, which then grow and kill neighboring neurons.
However, there are several inconsistencies with this hypothesis, not to mention the inability to show clinical benefit in several failed clinical trials by pharmaceuticals (i.e., from Pfizer, Eli Lilly, etc.), and it is in the field’s best interest to explore and test multiple hypotheses for pathology rather than drive the majority of research on this single amyloid theory.
Reviewing many scientifically peer-reviewed publications, Bursting Neurons and Fading Memories in Alzheimer’s Disease describes the “Inside-Out” hypothesis on how amyloid escapes the circulatory system through a dysfunctional blood-brain barrier to bind to the alpha 7 nicotinic acetylcholine receptor on pyramidal neurons.
Over time, excessive amounts of amyloid appear to be internalized, resulting in neuron death and lysis. This simple mechanism readily explains plaque composition, size, shape, and location. Based on the current direction of research in the field, this hypothesis appears years from any research and development.
About the author:
Michael R. D’Andrea received his PhD in Cell and Developmental Biology and his MS in Molecular Biology at Rutger’s University, New Brunswick, NJ, and his BA in Psycho-Biology at Western Maryland College, Westminster, MD. His dissertation work utilized molecular and histological assays to study the regulation of DNA topoisomerases in human cancers. His earlier career concerned the use of the high magnification electron microscopy to support oncogenesis in preclinical models, and then moved into a new field where he and his peers co-invented the chorionic villus sampling method at Thomas Jefferson for clinical chromosomal analysis. In the late 1980s and early 1990s, he mastered immunohistochemical methods at the light and electron microscopy levels when he began publishing his work in scientific journals.
However, it wasn’t until the mid-1990s, while working at Johnson & Johnson’s Pharmaceutical Research & Development as the Target Validation Team Leader, did he become engaged in Alzheimer’s disease (AD) research. His Team was responsible for supporting target discovery and validation, while supporting biomarker discovery in preclinical and experimental models using genomic, proteomic, and histopathological methods across many therapeutic areas and was honored with over a dozen Leadership and Scientific awards. Currently, he has over 100 scientifically peer-reviewed scientific publications and invited reviews, about a third of which concern the neuropathology of AD, and holds 11 scientific patents. He has reviewed hundreds of papers for many scientific journals, reviewed international grants in the AD field, and is currently on the editorial board of the journal, Biotechnic & Histochemistry.
He has been invited to speak at numerous International, National, and Regional meetings, as well as at Universities and other companies to discuss his novel observations concerning the origin of amyloid plaques, the existence of various plaque types, and most recently that AD is also an autoimmune disease; all of which is presented in this book. Recently, Michael established a contract research company, Slidomics, LLC (www.slidomics.com) to apply his histopathological and target validation expertise by providing high quality data and analysis much like what you see in this book.
The scientific study of the nervous system is entering a new golden age. Researchers and clinicians continue to advance the treatment of conditions such as Alzheimer’s syndrome, Parkinson’s disease, epilepsy, and traumatic brain injury. Public initiatives like the federal Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) program in the United States, announced in April 2013, ensure that funding and resources will continue to be applied to this rapidly growing field. Elsevier’s journals, books, eBooks, online references, and tools are respected around the world for everything from physiology and pathology to behavioral genetics and nerve repair. Our publications are a gateway to the latest advancements in neuroscience research and leading-edge data for professionals, students, and academics alike.