Dysfunctional intracellular calcium homoeostasis: a central cause of neurodegeneration in Alzheimer's disease.
The clinical symptoms of all forms of Alzheimer's disease (AD) result from a slowly progressive neurodegeneration that is associated with the excessive deposition of beta-amyloid (A beta) in plaques and in the cerebrovasculature, and the formation of intraneuronal neurofibrillary tangles, which are composed primarily of abnormally hyperphosphorylated tau protein. The sequence of cellular events that cause this pathology and neurodegeneration is unknown. It is, however, most probably linked to neuronal signal transduction systems that become misregulated in the brains of certain individuals, causing excessive A beta to be formed and/or deposited, tau to become aggregated and hyperphosphorylated and neurons to degenerate. We hypothesize that a progressive alteration in the ability of neurons to regulate intracellular calcium, particularly at the level of the endoplasmic reticulum, is a crucial signal transduction event that is linked strongly to the initiation and development of AD pathology. In this chapter we will discuss the key findings that lend support to this hypothesis.
O'Neill
C
C
Department of Biochemistry, University College, Lee Maltings, Prospect Row, Cork, Ireland.
Cowburn
R F
RF
Bonkale
W L
WL
Ohm
T G
TG
Fastbom
J
J
Carmody
M
M
Kelliher
M
M
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007424:Intracellular Fluid / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism*; D010766:Phosphorylation; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D016875:tau Proteins; D002118:Calcium