amyloid-beta-peptides and Hypercapnia

Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide (Abeta), play a critical role in the pathogenesis of Alzheimer's dementia. We report that transgenic mice overexpressing APP and Abeta have a profound attenuation in the increase in neocortical blood flow elicited by somatosensory activation. The impairment is highly correlated with brain Abeta concentration and is reproduced in normal mice by topical neocortical application of exogenous Abeta1-40 but not Abeta1-42. Overexpression of M146L mutant presenilin-1 in APP mice enhances the production of Abeta1-42 severalfold, but it does not produce a commensurate attenuation of the hyperemic response. APP and Abeta overexpression do not diminish the intensity of neural activation, as reflected by the increase in somatosensory cortex glucose usage. Thus, Abeta-induced alterations in functional hyperemia produce a potentially deleterious mismatch between substrate delivery and energy demands imposed by neural activity.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebrovascular Circulation; Female; Glucose; Humans; Hypercapnia; Hyperemia; Laser-Doppler Flowmetry; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Physical Stimulation; Presenilin-1; Somatosensory Cortex; Touch; Vibrissae

Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.

Topics: Acetylcholine; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autoradiography; Bradykinin; Brain; Calcimycin; Cerebrovascular Circulation; Endothelium, Vascular; Free Radical Scavengers; Gene Expression; Glucose; Hypercapnia; Ionophores; Laser-Doppler Flowmetry; Metalloporphyrins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitric Oxide Donors; Penicillamine; Peptide Fragments; Superoxide Dismutase; Superoxides; Vasodilator Agents