A potential role for crystallization inhibitors in treatment of Alzheimer’s disease
Introduction
Alzheimer’s disease is a neurodegenerative condition resulting in a progressive loss of mental function because of brain tissue deterioration. The causes of Alzheimer’s disease remain unknown and no scientific explanation has gained total acceptance. An early hypothesis was that the disease is caused by a reduction in the synthesis of the neurotransmitter acetylcholine. Support for this idea has not been forthcoming, because drugs used to treat cholinergic deficiencies have not been of assistance in Alzheimer’s disease patients.
A more recent hypothesis (propounded in 1991) suggested that the cause of Alzheimer’s disease was the abnormal accumulation of β-amyloid protein in the brain [1], [2], [3], [4], [5]. Such deposition has also been recently linked with dementia, including Alzheimer’s disease, and with metabolic disorders, particularly those of hyperglycemia and insulin resistance [6], [7].
Section snippets
Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized from tryptophan (via serotonin) and occurs mainly in the pineal gland. It has been postulated that melatonin has several properties, acting as an antioxidant [8], [9], [10], [11], a neuroprotective agent [12], [13], and a stabilizer of the circadian rhythm [14], [15]. Thus, melatonin is now considered to play an important role in aging processes.
Melatonin excretion decreases with age in all humans [16], [17], but this decline is
Hypothesis
As outlined above, the presence of lesions in the pineal gland, which may be attributable to different causes (old age, or exposure to cytotoxic materials or environmental contaminants), would result in development of calcification, the extent of which would increase with more severe injury, with lower concentrations of crystallization inhibitors (pyrophosphate and phytate) and/or with reduced ability of the immune system. Calcification of the pineal gland would lead to a loss of function,
Conclusion
Any pathological calcification in mammals, for example, cardiovascular calcification, calcinosis cutis, or calcium lithiasis, requires an inducer, usually a heterogeneous nucleant, to destabilize the surrounding fluid that is generally in a metastable state. To protect the body from such unwanted processes, natural crystallization inhibitors are present in the body that prevent or slow crystallization. If, in addition, pathological crystallization takes place in a cellular environment (within a
Conflict of interest statement
All authors declare that there are not any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
Acknowledgments
Financial support by Dirección General de Investigación (Proyecto CTQ2006-05640) and Gobierno de las Islas Baleares (PROGECIC-1C) is gratefully acknowledged.
References (28)
- et al.
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Trends Pharmacol Sci
(1991) - et al.
Alzheimer’s disease-do tauists and baptists finally shake hands?
Trends Neurosci
(2002) - et al.
Alpha- and beta-secretase activity as a function of age and beta-amyloid in down syndrome and normal brain
Neurobiol Aging
(2007) - et al.
Alzheimer disease and down syndrome: factors in pathogenesis
Neurobiol Aging
(2005) - et al.
Effects of age and dietary antioxidants on cerebral electron transport chain activity
Neurobiol Aging
(2001) - et al.
Pinealectomy: behavioral and neuropathological consequences in a chronic cerebral hypoperfusion model
Neurobiol Aging
(2002) - et al.
Pinealectomy causes hippocampal CA1 and CA3 cell loss: reversal by melatonin supplementation
Neurobiol Aging
(2007) - et al.
Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84
Psychoneuroendocrinology
(2006) - et al.
Melatonin rhythmicity: effect of age and Alzheimer’s disease
Exp Gerontol
(2003) - et al.
Variation of InsP4, InsP5 and InsP6 levels in tissues and biological fluids depending on dietary phytate
J Nutr Biochem
(2001)
Pineal calcification in Alzheimer’s disease: an in vivo study using computed tomography
Neurobiol Aging
Dementia, and cortical deposition of beta-amyloid protein
N Engl J Med
Utrecht diabetic encephalopathy study group. increased risk of Alzheimer’s disease in Type II Diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?
Biochem Soc Trans
(Pre)diabetes, brain aging, and cognition
Biochim Biophys Acta
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Alzheimer's disease via enhanced calcium signaling caused by the decrease of endoplasmic reticulum-mitochondrial distance
2016, Medical HypothesesCitation Excerpt :Neuronal cell death may occur through apoptosis and necrosis [6,7], the former being the predominant form in AD [3,8]. Despite extensive research into the etiologies of AD, the underlying pathogenic mechanisms involved remain obscure and no scientific explanation has gained total acceptance [9]. The main hypotheses that have been put forward to explain the causes of AD include amyloid cascade hypothesis [10], endoplasmic reticulum (ER) stress hypothesis [11,12], mitochondrial cascade hypothesis [13,14], and Ca2+ hypothesis of AD [15–17].
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