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(see below). However, therapies aimed solely at reducing amyloid beta have proven disappointing, suggesting a more complex process is involved. Neurofibrillary Tangles Neurons contain a cellular skeleton made up of microtubules, secured in place by specialized proteins called tau. In Alzheimer's disease, microtubules disintegrate and tau proteins "clump" together to form aggregates called neurofibrillary tangles or NFTs. NFTs function much the same as amyloid beta aggregates in that they initiate several process that lead to cellular dysfunction and death. Whether amyloid beta or NFTs arise first in Alzheimer's disease is unclear, and this remains a heavily debated topic within the scientific community. Acetylcholine deficit A theory once widely advocated, but which has proved to be disappointing at addressing underlying disease progression, is the cholinergic hypothesis. This view suggests that Alzheimer's disease is the consequence of insufficient synthesis of the neurotransmitter acetylcholine, which is fundamental in many aspects of cognition. Clinical trials have shown medications that support acetylcholine signaling reduce symptoms, but do not reverse or halt the disease. Therefore, inadequate cholinergic neurotransmission is now viewed as a consequence of generalized brain deterioration observed in Alzheimer's disease, rather than a direct cause. Nonetheless, drugs that modulate acetylcholine signaling are still a mainstay of symptomatic management of Alzheimer's disease. Oxidative Stress Oxidative stress is a process in which highly reactive molecules called free radicals damage cellular structures. Free radicals are byproducts of normal metabolism, but during states of metabolic abnormality such as mitochondrial dysfunction (see below), they are created more rapidly and in greater quantity. In the case of Alzheimer's disease, oxidative stress both facilitates some of the damage caused by amyloid beta and spurs its formation. Oxidative stress propagates Alzheimer's disease via another route as well. As neurons become damaged, free iron accumulates on their surfaces and within nearby cells called microglia. Free iron causes radical formation and drives oxidative stress. Inflammation The inflammatory process appears to play an important role in the development of Alzheimer's disease (AD). When high levels of amyloid beta accumulate in the brain, it activates the body's immune response, resulting in inflammation that damages neurons. Part of the inflammatory response to amyloid beta appears to be facilitated by tumor necrosis factor-alpha (TNF-α). TNF-α is a pro-inflammatory cytokine that is often found in high levels in serum and cerebral spinal fluid (CSF) of Alzheimer's patients; it represents a potential target for novel Alzheimer's disease therapies. Mitochondrial Dysfunction Mitochondria are the energy power plants of cells; they generate energy in the form of adenosine triphosphate (ATP), which is necessary for cellular function. Mitochondrial dysfunction has been implicated in many age-related diseases, including Alzheimer's disease. One line of evidence that supports a link between Abby's Magazine - November/December 2015 | Page 27