Alzheimer's disease as subcellular 'cancer': The scale-invariant principles underlying the mechanisms of aging

Abstract

Alzheimer's disease (AD) is characterized by the slow onset of neurodegeneration leading to dementia in many elderly people. 1) The pathological hallmarks of AD are: the extracellular β-amyloid deposition in the senile plaques; 2) the β-amyloid deposition in cerebral blood vessel walls especially in heredilary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D); 3) the intracellular neurofibrillary tangle formation composed of paired helical filaments (PHF), the principal component of which is a hyperphosphorylated form of the microtubule-binding protein, tau; 4) and neurological dysfuction and neuronal cell death in limited regions and pathways of the central nervous system. 5) Note that β-amyloid is a truncated form of a cell surface integral membrane glycoprotein: amyloid precursor protein (APP). 6) Despite these hallmarks, the pathogenesis of AD has been poorly understood. In the present paper, a theory of aging is proposed to give a coherent account of the origins and causes of neurodegeneration common to the diverse neurodegenerative disorders such as AD and prion (proteinaceous infectious particles) diseases 7),8) in comparison with the pathogenesis of cancers. 9) Surprisingly, the self-aggregation of denatured proteins - such as β-amyloid, PHF and prions -responsible for neuronal cell death resembles, in many respects, the development (or the clonal evolution) of malignant cells at the expense of the entire organism harboring them. Although neurodegenerative disorders and cancers apparently differ in pathology, they nevertheless seem to follow the same principles regardless of the level and scale of the biological organization. It is the general principles of heritable variations and natural selection 10) as well as the general principles of self-organization 11),12) that operate, not only on different molecules, but also at different hierarchical levels and scales of the biological organization, independent of the details of diseases. Traditionally, natural selection, along with self-organization, has been thought to underlie 'creative' aspects of biological phenomena such as the origin of life, 13) adaptive evolution of viruses, 14) immune recognition 15),16) and brain function. 17) It therefore must be surprising to find that the same principles will also underlie 'non-creative' aspects, for example, the development of cancer 18),19) and the aging of complex organisms. Although self-organization has extensively been studied in nonliving things such as chemical reactions 11) and laser physics, 12) it is undoubtedly true that the similar sources of the order are available to living things at different levels and scales. 20) Several paradigm shifts are, however, required to realize how the general principles of natural selection can be extensible to non-DNA molecules which do not possess the intrinsic nature of self-reproduction. One of them is, from the traditional, genetic inheritance view that DNA (or RNA) molecules are the ultimate unit of heritable variations and natural selection at any organization level, to the epigenetic (nongenetic) inheritance view 21),22) that any non-DNA molecule can be the target of heritable variations and molecular selection to accumulate in certain biochemical environment. Because they are all enriched with a β-sheet content, ready to mostly interact with one another, different denatured proteins like β-amyloid, PHF and prions can individually undergo self-templating or self-aggregating processes out of gene control. 23),24) Other paradigm shifts requisite for a breakthrough in the etiology of neurodegenerative disorders will be discussed. As it is based on the scale-invariant principles, the present theory also predicts plausible mechanisms underlying quite different classes of disorders such as amyotrophic lateral sclerosis (ALS), atherosclerosis, senile cataract and many other symptoms of aging. The present theory, thus, provides the consistent and comprehensive account of the origin of aging by means of natural selection and self-organization.