Like a computer, the brain needs a reliable source of power, which is provided as oxygen and glucose in the blood. However, in many neurological disorders this energy supply is disrupted. Brain blood flow is controlled by adjustment of the diameters of the vessels supplying the blood. Nortley et al. found that, both in humans developing Alzheimer's disease (AD) and in a mouse model of AD, brain capillaries become squeezed by pericytes (see the Perspective by Liesz). By defining the underlying mechanism, they suggest potential targets for therapy in early AD.
Science , this issue p. [eaav9518]; see also p. 
In Alzheimer’s disease (AD), the production of amyloid β (Aβ) oligomers and downstream tau dysfunction are thought to cause neuronal damage, in particular a loss of synapses and synaptic plasticity, which results in cognitive impairment. However, epidemiological data show that vascular factors are important contributors to AD risk, and biomarker research has shown that the first change in AD is a decrease of cerebral blood flow. Because most of the vascular resistance within the brain is located in capillaries, this could reflect a dysfunction of contractile pericytes on capillary walls. Indeed, pericytes are known to regulate cerebral blood flow physiologically and to severely restrict blood flow after stroke.
We examined the role of pericytes in Alzheimer’s disease by examining cerebral capillaries in humans and mice developing AD, and by applying Aβ to capillaries. We used freshly fixed brain biopsies from cognitively impaired living humans who were depositing Aβ plaques, and also carried out in vivo imaging in a knock-in mouse model of AD. We measured capillary diameters at positions near pericytes in order to assess whether the capillaries became constricted in AD, because this would lead to a decrease of cerebral blood flow and hence a decrease of the glucose and oxygen supply to the brain tissue. In addition, to investigate one mediator already thought to be important in AD, we applied Aβ to human brain slices made from normal tissue that was removed from patients undergoing neurosurgical glioma resection, as well as to rodent brain slices. Aβ was applied in the oligomeric form, which is thought to contribute to cognitive decline. This allowed us to examine whether Aβ itself might alter cerebral blood flow, and to use pharmacology to investigate the mechanism of any such effect.
Both in humans developing AD and in the mouse model of AD, capillaries were constricted specifically at pericyte locations, but arterioles and venules were unchanged in diameter. Thus, the reduction of cerebral blood flow known to occur in AD is produced by capillaries rather than by arterioles. The capillary constriction increased rapidly with the severity of Aβ deposition, and we calculated that in the human cortex this constriction would have the effect of reducing cerebral blood flow by approximately half; this is comparable to the decrease of blood flow measured experimentally in affected parts of the AD brain. In the AD mouse cerebellum, which lacks Aβ deposition at the age examined, there was no capillary constriction, supporting the idea of a causal link between Aβ level and constriction of capillaries. Aβ itself was found to constrict both human and rodent capillaries through a mechanism involving the generation of reactive oxygen species (ROS), mainly by NOX4 (reduced nicotinamide adenine dinucleotide phosphate oxidase 4). The ROS then triggered the release of endothelin-1, which acted on ETA receptors to evoke pericyte contraction, thus causing capillary constriction. The Aβ-evoked constriction could be halted by blocking NOX4 and ETA receptors, and was reversed by applying the vasodilator C-type natriuretic peptide.
These data reconcile genetic evidence for a role of Aβ in triggering neuronal damage and cognitive decline in AD with the fact that a decrease of cerebral blood flow is the first clinically detectable change in AD. They imply that attention should be given to vascular mechanisms in AD as well as to signaling pathways that act directly on neurons or glia, and suggest novel therapeutic approaches for treating early AD by targeting drugs to brain pericytes. Our findings also raise the question of what fraction of the damage to synapses and neurons in AD reflects direct actions of Aβ and downstream tau, and what fraction is a consequence of the decrease of energy supply that Aβ produces by constricting capillaries.
Live human and rodent brain capillaries become constricted in Alzheimer’s disease.
Tissue from humans and rodents (left) that were healthy or developing Alzheimer’s disease (AD) was imaged in vivo and as brain slices (center), revealing that pericytes constrict brain capillaries early in AD via a mechanism involving ROS generation and release of endothelin-1, which activates ETA receptors (right).
Cerebral blood flow is reduced early in the onset of Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.