Dysregulation of cellular calcium homeostasis in Alzheimer's disease: Bad genes and bad habits

M. P. Mattson, S. L. Chan

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasticity, and the regulation of various metabolic pathways. The findings reviewed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer's disease (AD). Associations between the pathological hallmarks of AD (neurofibrillary tangles [NFT] and amyloid plaques) and perturbed cellular calcium homeostasis have been established in studies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the β-amyloid precursor protein (APP) and presenilins on neuronal plasticity and survival have provided insight into the molecular cascades that result in synaptic dysfunction and neuronal degeneration in AD. Central to the neurodegenerative process is the inability of neurons to properly regulate intracellular calcium levels. Increased levels of amyloid β-peptide (Aβ) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnerable to apoptosis and excitotoxicity. Subtoxic levels of Aβ may induce synaptic dysfunction by impairing multiple signal transduction pathways. Presenilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links between aberrant calcium regulation and altered APP processing are emerging. Environmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual activity (bad habits); in each case, the environmental factor impacts on neuronal calcium homeostasis. Low calorie diets and intellectual activity may guard against AD by stimulating production of neurotrophic factors and chaperone proteins. The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic strategies for eradicating this growing epidemic of the elderly.

Original languageEnglish (US)
Pages (from-to)205-224
Number of pages20
JournalJournal of Molecular Neuroscience
Issue number2
StatePublished - 2001
Externally publishedYes


  • Amyloid
  • Apoptosis
  • Excitotoxicity
  • Oxidative stress
  • Presenilin
  • Synaptic plasticity

ASJC Scopus subject areas

  • General Neuroscience
  • Biochemistry
  • Genetics


Dive into the research topics of 'Dysregulation of cellular calcium homeostasis in Alzheimer's disease: Bad genes and bad habits'. Together they form a unique fingerprint.

Cite this