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Review
. 2010 Sep;120(3):287-96.
doi: 10.1007/s00401-010-0718-6. Epub 2010 Jul 11.

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

Costantino Iadecola  1
Affiliations
Review

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

Costantino Iadecola. Acta Neuropathol. 2010 Sep.

Abstract

There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier, and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

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Figures

Fig. 1
Fig. 1
The neurovascular unit is constituted by endothelial cells, myocytes, neurons and their processes, astrocytes, and perivascular cells (microglia, macrophages, mast cells, etc.). In arterioles and capillaries, the foot processes of astrocytes envelop the majority of the abluminal vascular surface. In capillaries, myocytes are replaced by pericytes. The function of the neurovascular unit is to maintain the homeostasis of the cerebral microenvironment. Thus, the neurovascular unit is involved in cerebral blood flow regulation, blood–brain barrier (BBB) exchange, immune surveillance, trophic support, and hemostatic balance. Cardiovascular risk factors and Aβ alter the structure and function of the neurovascular unit leading to neurovascular dysfunction
Fig. 2
Fig. 2
Mechanisms of white matter damage produced by cardiovascular risk factors and Aβ. Oxidative stress and inflammation induced by these factors are responsible for disruption of the functions of the neurovascular unit (see Fig. 1), which, in turn, leads to local hypoxia–ischemia, axonal demyelination, and reduced repair potential of the white matter by altering oligodendrocyte progenitor cells. Data in autoimmune models of demyelination suggest that loss of myelin increases the energy consumption of the affected axons and aggravates local hypoxia. The resulting white matter damage contributes to both VCI and AD
Fig. 3
Fig. 3
In vascular dementia, cerebrovascular risk factors induce neurovascular dysfunction (see Fig. 2), leading to cerebrovascular insufficiency, which, in turn, leads to brain dysfunction and damage. In AD, cleavage of the amyloid precursor protein by β- and γ-secretases leads to Aβ accumulation, which also causes brain dysfunction and damage. Although individually these pathways are capable of inducing cognitive impairment, their interaction enhances their pathogenic effects. Thus, Aβ induces vascular dysregulation and aggravates the vascular insufficiency, thereby enhancing the brain dysfunction and damage associated with vascular risk factors. On the other hand, the hypoxia–ischemia resulting from the vascular insufficiency increases Aβ cleavage from APP and reduces Aβ clearance through the cerebral vasculature, promoting Aβ accumulation and the attendant deleterious effects on the brain
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