Physiologic origins of age-related beta-amyloid deposition.

BACKGROUND

Brain beta-amyloid (Abeta) deposition is an extremely common accompaniment of aging in humans and many other mammalian species. We hypothesized that normal physiological changes of aging cause Abeta deposition.

OBJECTIVE

Three normal physiological aging changes were induced in young adult rabbits to determine their effects on brain Abeta concentrations and deposition. The three changes were cortical cholinergic deafferentation, hypercholesterolemia and estrogen deprivation.

METHODS

Cortical cholinergic deafferentation was achieved through intracerebroventricular immunotoxin injection. Hypercholesterolemia was induced with a 2% cholesterol diet. Estrogen deprivation was modeled with ovariectomy.

RESULTS

Cortical cholinergic deafferentation resulted in an 8-fold increase in cortical Abeta(42) concentrations and cerebrovascular Abeta deposition. Hypercholesterolemia increased cortical Abeta(42) 4.6-fold while ovariectomy increased cortical Abeta(42) 1.6-fold.

CONCLUSION

At least three physiological changes of normal aging may underlie age-related brain Abeta accumulation and Alzheimer's disease.