Abstract：
:Alzheimer's disease (AD) includes etiologically heterogeneous disorders characterized by senile or presenile dementia, extracellular amyloid protein aggregations containing an insoluble amyloid precursor protein derivative, and intracytoplasmic tau protein aggregations. Recent studies also show excess neuronal aneuploidy, programmed cell death (PCD), and mitochondrial dysfunction. The leading AD molecular paradigm, the "amyloid cascade hypothesis", is based on studies of rare autosomal dominant variants and does not specify what initiates the common late-onset, sporadic form. We propose for late-onset, sporadic AD a "mitochondrial cascade hypothesis" that comprehensively reconciles seemingly disparate histopathologic and pathophysiologic features. In our model, the inherited, gene-determined make-up of an individual's electron transport chain sets basal rates of reactive oxygen species (ROS) production, which determines the pace at which acquired mitochondrial damage accumulates. Oxidative mitochondrial DNA, RNA, lipid, and protein damage amplifies ROS production and triggers three events: (1) a reset response in which cells respond to elevated ROS by generating the beta-sheet protein, beta amyloid, which further perturbs mitochondrial function, (2) a removal response in which compromised cells are purged via PCD mechanisms, and (3) a replace response in which neuronal progenitors unsuccessfully attempt to re-enter the cell cycle, with resultant aneuploidy, tau phosphorylation, and neurofibrillary tangle formation. In addition to defining a role for aging in AD pathogenesis, the mitochondrial cascade hypothesis also allows and accounts for histopathologic overlap between the sporadic, late-onset and autosomal dominant, early onset forms of the disease.
journal_name
Med Hypothesesjournal_title
Medical hypothesesauthors
Swerdlow RH,Khan SMdoi
10.1016/j.mehy.2003.12.045keywords:
subject
Has Abstractpub_date
2004-01-01 00:00:00pages
8-20issue
1eissn
0306-9877issn
1532-2777pii
S0306987704001252journal_volume
63pub_type
杂志文章abstract：:NETosis, being an alternative form of cell death is the creation of web-like chromatin decondensates by suitably primed neutrophils as a response to stimulus aimed at containing and eliminating the same. In certain situations, it causes more harm than benefit in the form of bystander damage directly or via activation ...
journal_title：Medical hypotheses
pub_type： 信件
doi：10.1016/j.mehy.2020.109968
更新日期：2020-11-01 00:00:00
abstract：:Chemo- and radio-resistant cancer cells within solid tumors undermine the effectiveness of these approaches to achieving oncolysis. These resistant cells and clusters of cells typically thrive at low oxygen tensions and are reliant on anaerobic metabolic pathways that churn out lactate. This hypoxic state is one that ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2006.09.013
更新日期：2007-01-01 00:00:00
abstract：:Nasopharyngeal angiofibroma is a histologically benign tumor composed of stroma and vessels. The vascular component of the lesion is prone to bleeding and responsible for its clinical "malignancy". Some nasopharyngeal angiofibromas are resistant to surgical therapy because of extensive growth and occasionally bone des...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2007.06.011
更新日期：2008-01-01 00:00:00
abstract：:Information about the etiology of pressure sores has been contradictory and is inconsistent with the idea that pressure sore formation is due extensively to depriving a tissue region of blood. Based on these observations and on studies done in the cooperating laboratories, an hypothesis has been formulated that integr...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(83)90067-1
更新日期：1983-06-01 00:00:00
abstract：:In this communication I propose a technique for manipulating the idiotype anti-idiotype network with the aim of enhancing the immune response to tumors. The theoretical basis for this technique follows from Jerne's network theory of the immune system. By tolerizing the host to immunoglobulin bearing idiotypes directed...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(85)90029-5
更新日期：1985-11-01 00:00:00
abstract：:Through the analysis of accumulated experimental data of cell growth, a model of unrestricted cell growth is presented here. This model is based hypothetically on the cellular commitment to senescence as in the previously presented commitment theory. Cells are divided into 3 types, namely uncommitted cells, committed ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(92)90034-a
更新日期：1992-08-01 00:00:00
abstract：:Benign prostatic hyperplasia (BPH) is one of the most common problems faced by aging men and can be associated with bothersome lower urinary tract symptoms that affect quality of life by interfering with normal daily activities and sleep patterns. Despite the clinical importance of BPH, its pathogenesis is still poorl...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2007.07.012
更新日期：2008-01-01 00:00:00
abstract：:p27(Kip1) (here after referred to as p27) is a member of a family of cyclin-dependent kinase inhibitors that control cell cycle. There is a considerable evidence that p27 plays a pivotal role in multiple foundational cellular processes, including cell proliferation, cell differentiation, and apoptosis. A large number ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2007.01.034
更新日期：2007-01-01 00:00:00
abstract：:Vitamin A is a fat-soluble vitamin required for many physiological functions. The intracellular transport of vitamin A is assisted by proteins called cellular retinol-binding proteins (CRBP I/II). The absorption, storage and usage of vitamin A are regulated by a protein called lecithin:retinol acyltransferase (LRAT), ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2016.01.013
更新日期：2016-03-01 00:00:00
abstract：:The levator ani muscles in women are overloaded by constant supporting abdominal contents, and counteracting rises of abdominal pressure at the level of the urethra. The excessive load leads to a decrease in their type II fibers. This results in stress urinary incontinence due to loss of the fibers responsible for add...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(93)90225-f
更新日期：1993-06-01 00:00:00
abstract：:Acute renal failure (ARF) is a rapid loss of kidney function. The reasons and mechanism by which this occurs has not been clarified so far thus creating obstacles to management of this disease. Presently, the experimental research using the accepted renal ischemia reperfusion injury (I/R injury) model represented for ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2012.12.041
更新日期：2013-04-01 00:00:00
abstract：:In observing the phenomenon of alterations of tumor cell phenotypes, one may envision a mechanism that induces the change in tumor cell characteristics and the appearance of metastasis. Schirrmacher (1) has suggested that the effect of the microenvironment on tumor cells influences the control of gene expression and t...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(81)90010-4
更新日期：1981-05-01 00:00:00
abstract：:For diagnosis of Human Immunodeficiency Virus (HIV) infection by the recently developed Polymerase Chain Reaction (PCR), the two commonly used clinical samples are either the peripheral blood monocytes (PBMC) or the plasma of the infected individuals. In the former instance, DNA is extracted from PBMC. The integrated ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(93)90188-v
更新日期：1993-01-01 00:00:00
abstract：:Inadequately responsive glycaemic control is an important factor in the causation of diabetic end-organ damage. Artificial or hybrid bioartificial pancreases can provide responsive glycaemic control that can reduce the enormous personal suffering and socio-economic costs of diabetes. However, they share the shortcomin...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2006.08.047
更新日期：2007-01-01 00:00:00
abstract：UNLABELLED:T helper (Th) lymphocytes have been classified into distinct subsets, Th1 and Th2 on the basis of the cytokines they produce. According to the cross-regulatory properties of Th1 and Th2 cells, one would assume that to be affected by a Th1 type disease increases susceptibility to a Th1 type disease and inhibi...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2006.03.039
更新日期：2006-01-01 00:00:00
abstract：:Some genes such as those for histones and RNAs are conserved unchanged through much of evolution and have numerous tandem repeat copies in the genome. It is proposed that as yet undetected 'polystrand' enzymes use such multiple copies as a means of conserving their sequence by comparing the copies and eliminating erro...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(90)90099-z
更新日期：1990-08-01 00:00:00
abstract：:It is generally accepted that a placebo in a standard, randomized, controlled trial (RCT), being an inert substance, cannot itself produce any effects. Yet, the magnitude of the placebo effect has increased remarkably in the last three decades. We propose that macroscopic information entanglement potentially explains ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2011.06.047
更新日期：2011-10-01 00:00:00
abstract：:Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson's disease patients, weight loss and metabolic...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2019.109436
更新日期：2020-01-01 00:00:00
abstract：:The secretion of Follicle Stimulating Hormone by the pituitary gland is not regulated entirely by the negative feedback from gonadal steroids. There is ample evidence that the secretion of FSH is regulated by a non-steroidal hormone of gonadal origin termed "inhibin". Using a radioimmunoassay procedure, immunoreactive...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(84)90119-1
更新日期：1984-10-01 00:00:00
abstract：:In mathematics and physics, chaos theory deals with the behavior of certain nonlinear dynamical systems that under certain conditions exhibit a phenomenon known as chaos, which is characterised by a sensitivity to initial conditions. Mathematicians paradoxically call such states of order chaos and distinguish them fro...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2006.02.032
更新日期：2006-01-01 00:00:00
abstract：:It is proposed that gastrin promotes the uptake of divalent and trivalent metal ions from the gastrointestinal lumen by catalyzing the binding of metal ions to luminal albumin and transferrin respectively. The following observations are consistent with this hypothesis: 1. Gastrin binds both divalent and trivalent meta...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(92)90161-5
更新日期：1992-05-01 00:00:00
abstract：:From biographical data sources on ranking scientists, I was able to identify 35 centenarians. Among these, only one (Michel Chevereul from France) lived before the 20th century. Since the remaining 34 individuals became centenarians only from 1965, I propose that centenarian scientists are an unusual cluster, first fo...
journal_title：Medical hypotheses
pub_type： 历史文章,杂志文章
doi：10.1054/mehy.2001.1480
更新日期：2001-12-01 00:00:00
abstract：UNLABELLED:Physiological acts present the puzzle that we are unable to explain how we performed them, how we solved the technical difficulties involved in their execution. For instance, when we sing, we produce various musical notes by changing the shape of the larynx. The normal person does not even know what the lary...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/s0306-9877(02)00156-1
更新日期：2002-12-01 00:00:00
abstract：:The 2013 American Heart Association Blood Cholesterol Guidelines increased the number of patients recommended for statin therapy in the United States to 56million. Two common statin side effects are muscle pain, referred to as "statin-associated muscle symptoms", and increased risk for new onset type-2-diabetes mellit...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2017.07.007
更新日期：2017-09-01 00:00:00
abstract：:A large number of epileptic patients suffer from refractory epilepsy, despite optimal treatment; thus these patients require new therapeutic approaches. Focal seizure activity is typically initiated in a fixed and localized region, which subsequently spreads to neighboring regions or more distant areas. At the initial...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2013.07.046
更新日期：2013-11-01 00:00:00
abstract：:A high incidence of sudden unexplained nocturnal deaths has been reported among young Asian males. These deaths are known as Pokkuri in Japan, Bangungut in the Philippines and Sudden Unexplained Nocturnal Death in the United States. Post mortem analysis has demonstrated cardiac conduction defects in many of the victim...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/0306-9877(88)90071-0
更新日期：1988-06-01 00:00:00
abstract：:A lowered risk of multiple sclerosis (MS) has been reported in the Hutterite community residing mainly in southern Canada. In another anabaptist community, the Old Colony Mennonites (OCM), settled in Canada and spread to Latin America, only a large pedigree with an increased risk of autoimmune diseases, including type...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2006.03.044
更新日期：2006-01-01 00:00:00
abstract：:A holistic-organismic approach is suggested as foundation for intensified, systematic inquiry into relationships among adult attachment styles and various dimensions of physical and mental health. Exploratory findings of differences in stamina associated with adult attachment style are noted. The extent to which attac...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/s0306-9877(03)00125-7
更新日期：2003-07-01 00:00:00
abstract：:In the present report we have developed a mathematical model to describe the processes involved during high steroid therapy. We have shown that the model can predict clinical observations as well as determine the optimum steroid regimen without relying on trial and error methods. The model incorporates rate processes ...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1054/mehy.2001.1308
更新日期：2001-07-01 00:00:00
abstract：:Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents the largest current health challenge for the society. At the moment, the therapeutic strategies to deal with this disease are only supportive. It is well known that zinc (Zn) possesses a variety of dir...
journal_title：Medical hypotheses
pub_type： 杂志文章
doi：10.1016/j.mehy.2020.109848
更新日期：2020-11-01 00:00:00
