By Michael Rafii, M.D., Ph.D, ADCS Associate Medical Director

Among the major uncertainties surrounding Alzheimer’s disease is whether and how the amyloid plaques found in the brains of patients with the disorder actually damage neurons. There are many theories; below are two of the leading ideas.


Calcium Overload

Calcium ions play an essential role in transmitting signals from one neuron to another. Many studies have suggested that alterations in calcium regulation may be involved in the neurodegeneration that characterizes Alzheimer’s disease, but the mechanism behind that association has been unclear. and new surgical or radiation therapy methods.

A few major studies have recently looked at calcium in AD. After first verifying that their strategy could accurately depict neuronal calcium levels, including specific levels in the actual extensions that carry neuronal signals, researchers showed that dendrites were almost six times more likely to have excessive levels of calcium in transgenic mice with amyloid plaques than in normal mice.

They then found how this calcium overload probably interferes with neuronal communication. Normally specific signals being transmitted are reflected by distinct calcium levels in structures within the extensions, called dendritic spines, but in mice with the plaque-associated elevations, calcium levels were the same throughout a dendrite instead of changing at the locations of the spines. Those dendrites in which calcium levels were highest also had structural changes similar to those seen in the brains of patients who have died with Alzheimer’s disease.

In a related finding, abnormal calcium signaling was also linked to the more common spontaneously occurring form of AD. In this study, researchers discovered a mutation associated with late onset, sporadic AD that disrupted a previously uncharacterized brain calcium channel and led to subsequent accumulation of amyloid beta protein, and increases the risk of developing AD by 44%.

Cheung et al. Mechanism of Ca2 Disruption in Alzheimer’s Disease by Presenilin Regulation of InsP3 Receptor Channel Gating. Neuron, Vol 58, 871-883, 26 June 2008
Dreses-Werringloer et al. A Polymorphism in CALHM1 In?uences Ca2+ Homeostasis, A? Levels, and Alzheimer’s Disease Risk. Cell, 133, 1149-1161, June 27, 2008

Cell Death Pathway

Another group injected amyloid peptide into neurons that had been removed from human brains and then measured their survival in culture. Neurons infused with a benign version of amyloid peptide, called A 40, or with control proteins, sustained no ill effects. Cells that were shot up with the plaque-forming A 42, however, suffered grievously: 1500 protein molecules per cell killed half the cells–and neurons in the brains of people with AD can harbor far more than 1500 A 42 molecules, the authors estimate.

Additional experiments suggest that A 42 inside the cell activates a well-studied cell death pathway. When the researchers delivered A 42 together with molecules that block the function of a cell death-inducing protein called Bax, neurons no longer died at the hand of A 42. A second protein, p53, that activates Bax is also implicated: Neurons that carry a mutation in p53 that obliterates its capacity to turn on Bax production similarly withstood the A 42 assault. Together the results directly demonstrate that A 42 kills cells from the inside by activating a cell death signaling pathway.

Y. Zhang, R. McLaughlin, C. Goodyer, A. LeBlanc, Selective cytotoxicity of intracellular amyloid peptide1-42 through p53 and Bax in cultured primary human neurons. J. Cell Biol. 156, 519-529 (2002)