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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Neurotherapeutics. Author manuscript; available in PMC Jul 1, 2009.
Published in final edited form as:
PMCID: PMC2536515

New Therapeutic Targets in the Neurovascular Pathway in Alzheimer’s Disease


Recent findings indicate that neurovascular dysfunction is an integral part of Alzheimer’s disease (AD). Changes in the vascular system of the brain may significantly contribute to the onset and progression of dementia and to the development of a chronic neurodegenerative process. In contrast to the neurocentric view which proposes that changes in chronic neurodegenerative disorders, including AD, can be attributed solely to neuronal disorder and neuronal dysfunction, the neurovascular concept proposes that dysfunction of non-neuronal neighboring cells and disintegration of neurovascular unit function may contribute to the pathogenesis of dementias in the elderly population, and understanding these processes will be crucial for the development of new therapeutic approaches to normalize both vascular and neuronal dysfunction. In this review, I discuss briefly the role of vascular factors and vascular disorder in AD, the link between cerebrovascular disorder and AD, the clearance hypothesis for AD, the role of RAGE (receptor for advanced glycation end products) and LRP (low density lipoprotein receptor related protein 1 (LRP) in maintaining the levels of amyloid β-peptide (Aβ) in the brain by controlling its transport across the blood-brain barrier (BBB) and the role of impaired vascular remodeling and cerebral blood flow dysregulation in the disease process. The therapeutic strategies based on new targets in the AD neurovascular pathway, such as receptors RAGE and LRP, and on a few selected genes implicated in AD neurovascular dysfunction, e.g., mesenchyme homebox gene 2 and myocardin, are also discussed.

Keywords: Blood-brain barrier, RAGE, LRP, amyloid β-peptide, ischemia, angiogenesis, dementia


Several epidemiologic studies, including the large population-based Rotterdam study,1,2 have suggested that vascular risk factors might be responsible for cognitive decline in the elderly population. Old age, atherosclerosis, stroke, hypertension, transient ischemic attacks, cardiac disease, the ε4 allele of the apolipoprotein E gene, elevated homocysteine levels, hyperlipidemia, metabolic syndrome, obesity and diabetes, to name a few, are risk factors for both vascular dementia and Alzheimer’s disease (AD).36 Whether controlling vascular risk factors, vascular brain disorder and/or metabolic syndrome in early diagnosed AD individuals will prevent progressive cognitive decline and dementia is unclear at present.

Progressive cognitive decline in AD is associated with neurovascular dysfunction,3,4 chronic neurodegenerative process, accumulation of neurotoxic amyloid β-peptide (Aβ) on blood vessels and in brain parenchyma,79 intraneuronal lesions — neurofibrillar tangles (NFT)1012 and vascular deposition of amyloid resulting in cerebral amyloid angiopathy (CAA).13,14 Whether neurovascular dysfunction and vascular lesions precede a chronic neurodegenerative process, as suggested by a number of recent studies reviewed elsewhere,15 or they develop in response to neurodegeneration is controversial and has been a subject of many debates. But, without knowing the exact relationship between vascular and neuronal lesions in AD it might be difficult to develop new therapeutic approaches to treat cognitive decline, especially in AD cases with prominent cerebrovascular and metabolic co-morbidity.

Role of brain ischemia

Large cerebral arteries in AD do not develop CAA, but are frequently affected by atherosclerosis.16,17 The Nun Study found that cerebrovascular disease determines the presence and severity of AD, and that demented AD individuals with one or two lacunar infarcts have a much steeper drop in cognitive function compared to individuals with no brain infarcts irrespective of the number of NFT in neocortex.18 The Rotterdam Scan, a prospective, population-based study on 1,015 patients, demonstrated that silent brain infarcts detected on magnetic resonance imaging (MRI) doubled the risk for dementia in elderly people with a hazard factor of 2.26.19 The Rotterdam study on 1,730 subjects found that cerebral hypoperfusion preceded the onset of clinical dementia and that reductions in cerebral blood flow (CBF) velocity occurred before cognitive decline and hippocampal and amygdalar atrophy were documented on MRI.2 But, the exact pathway(s) by which atherosclerosis and arteriolosclerosis contribute to cognitive decline, and the relationship between vascular brain damage, white matter hyperintensities on MRI and cognitive decline, are still not completely understood.20 Figure 1 illustrates possible pathways by which atherosclerosis may lead to dementia. Whether progression of vascular disorder and dementia in AD could be controlled by a new class of agents exerting combined anti-coagulant, anti-inflammatory and neuroprotective activities in the ischemic brain, such as activated protein C (APC),21 remains to be explored.

Figure 1
Schematic illustrating different pathways how atherosclerosis may lead to cognitive decline in the elderly

In rodents, ischemia increases Aβ production,3 accumulation of hyperphosphorylated tau in cortical neurons and filament formation similar to that present in human neurodegenerative tauopathies and AD,22,23 suggesting that hypoperfusion may generate neuropathological changes similar to those as seen in AD individuals. Aβ is a potent vasoconstrictor in brain.24 In Aβ-precursor protein (APP) expressing mice, reductions in endothelium-dependent regulation of cortical microcirculation25 and CBF dysregulation in response to brain activation have been reported prior to neuropathological changes.26,27 Similarly, neurovascular uncoupling, reductions in CBF and low brain uptake of glucose, have been shown in sporadic AD prior to cognitive decline.2830

Clearance hypothesis for AD

Most AD cases (~ 99%) present with late onset (i.e., > 65 years of age), without clear evidence of genetic transmission.31 Late-onset AD individuals do not normally have increased production of Aβ. Instead, Aβ likely accumulates in brains of AD individuals due to its deficient clearance from brain,3235 as illustrated in Figure 2. Recent evidence suggests that plaques are generated on blood vessels due to faulty Aβ clearance across the BBB, or during its transport by passive diffusion across Virhoff-Robin perivascular arterial spaces.15

Figure 2
The clearance hypothesis for Alzheimer’s disease (AD)

Aβ is central to the development of brain pathology in AD.79,12,33,36,37 Patients with sporadic AD and familial AD (FAD; < 1% of all AD cases) typically develop focal increases in brain Aβ levels mid-way through the disease process or at a later stage. Elevated Aβ levels in brain generate neurotoxic Aβ oligomer species, which may disrupt normal brain function37 and/or lead to Aβ deposits in the form of senile plaques. In murine models of AD, such as APP-overexpressing mice with Swedish mutation (APPsw+/−) and transgenic APP mice harboring vasculotropic Dutch, Iowa and Swedish triple APP mutations, dense plaques initially develop on blood vessels or as classical CAA.3840

In > 80% of AD cases, the pial and intracerebral arteries are affected by CAA.14 Pathogenic levels of vasculotropic mutant forms of Aβ (e.g., Dutch, Iowa, Arctic, Flemish, Italian) accelerate degeneration of the vessel wall contributing to hemorrhagic strokes, as in familial forms of AD.13

How we might prevent Aβ accumulation by accelerating its clearance from brain is an emerging area of research which holds promise for the development of new future therapies for AD (see below).

RAGE and LRP regulate Aβ blood-brain barrier transport


The receptor for advanced glycation end products (RAGE) is normally expressed at low levels in brain except for the endothelium of brain capillaries and small arterioles (Sagare, Deane, Bell, Zlokovic, unpublished observations). But, under pathophysiological conditions such as those associated with the accumulation of RAGE ligands on blood vessels (e.g., deposition of proteins modified by glycation and oxidation – AGE proteins or Aβ), the expression of cerebrovascular RAGE is increased. In AD and AD models RAGE expression increases by several-fold in affected cerebral vessels and in microglia and neurons.4146 RAGE binds different forms of Aβ and its reaction with Aβ at the luminal membrane of the BBB (Figure 3) mediates (1) re-entry of circulating Aβ into the brain across the BBB followed by Aβ binding to neurons; (2) NF-κB-dependent activation of endothelium with expression of proinflammatory cytokines and adhesion molecules; and (3) secretion of endothelin-1 resulting in CBF reductions. In addition to mice and rats, transport of Aβ peptides from blood to brain across the BBB has been shown in other species including guinea pigs and non-human primates.47,48 Compared to other small peptides, such as vasopressin or enkephalins,49,50 transport of Aβ40 across the mouse BBB was 2–3-fold faster, although it was only a fraction of the rate determined for amino acids transport either across the BBB or the choroid plexus.51,52

Figure 3
Transport equilibrium for amyloid β-peptide (Aβ) at the blood-brain barrier (BBB)

RAGE is an important therapeutic target in AD. RAGE/Aβ interaction on neurons can kill neurons directly by producing oxidative damage or indirectly by activating microglia.41 Inhibition of RAGE/Aβ interaction in the affected blood vessels blocks Aβ influx across the BBB and the associated oxidant stress and neuroinflammation.43 RAGE/Aβ blockers are currently being tested in AD patients for safety and efficacy (A Double-Blind, Placebo-Controlled, Randomized, Multi-center Study Evaluating the Efficacy and Safety of Eighteen Months of Treatment with PF-04494700 (TTP488) in Participants with Mild-to-Moderate Alzheimer’s Disease conducted by the ADCS; patient enrollment began in December 2007).


Low density lipoprotein receptor related protein 1 (LRP), a member of the LDL receptor family, is a major clearance receptor for Aβ at the BBB.53 Aβ binding to LRP is the first step in Aβ clearance from brain mediated by transvascular Aβ transport across the BBB39,5355 as illustrated in Figure 3. Interestingly, substitution at codon 22 of LRP, as in Dutch type FAD, reduces clearance of Aβ from the CSF and brain into blood.56 Reduced expression of LRP was found during normal aging in rodents, non-human primates and in AD individuals associated with positive staining of cerebral vessels for Aβ40 and Aβ42.39,45,53 Mice with severely depleted LRP levels at the BBB develop Aβ accumulations when crossed with APP overexpressing mice.57 Binding of Aβ to apolipoprotein J and E and α2M critically alters Aβ clearance rates from the brain and can influence its vascular and parenchymal accumulation.35,55 Finally, LRP mediates Aβ systemic clearance from the liver.58

Beta-secretase cleaves the N-terminal extracellular domain of LRP59 and releases soluble LRP (sLRP) in plasma. Recently, it has been shown that sLRP normally binds 70–90% of Aβ in human plasma.60 Aβ binding to sLRP is significantly reduced in late-stage LOAD cases, which, in turn, may elevate brain Aβ due to reductions in the endogenous peripheral sink activity of sLRP. Recombinant LRP clusters can effectively sequester Aβ in AD plasma and in APPsw+/− mice, promoting Aβ efflux from the mouse brain.60 Thus, LRP fragments may have therapeutic potential as novel Aβ clearance agents and/or sLRP replacement therapy for AD.

Mdr1a/mdr1b null mice lack P-gp at the BBB and express lower levels of LRP in brain capillaries.54 Mdr1a/mdr1b null mice exhibit reduced clearance of Aβ from brain, whereas APP mice lacking P-gp have accelerated accumulation of Aβ and amyloid deposition. Thus, mdr1a and mdr1b genes may influence Aβ clearance either directly through P-gp and/or indirectly through LRP.

Impaired vascular remodeling

Reduced microvascular density, fragmented and atrophic string vessels, irregularity of capillary endothelial surfaces, reductions in the vessel diameter, thickening of capillary basement membranes and collagen accumulation in basement membranes have been described in AD.61,62 It has been suggested that the degeneration of brain capillary endothelium seen in AD and AD models may reflect aberrant sprouting angiogenesis in response to chronic brain hypoxia.15 A recent report found extremely low levels of expression of the mesenchyme homebox gene 2 (MEOX2) in the BBB of AD individuals.63 MEOX2 normally regulates vascular cell differentiation and repair and its expression in the adult brain is restricted to the vascular system. Low levels of MEOX2 in AD endothelium mediate abnormal responses to angiogenic factors such as vascular endothelial growth factor, resulting in premature vessel regression, reduced resting CBF and improper formation of the BBB.63 Low levels of MEOX2 also promote proteasomal degradation of LRP, which lowers the Aβ clearing capability at the BBB leading to Aβ accumulation on the blood vessels. Accumulation of Aβ on the abluminal membrane of the blood vessels is anti-angiogenic which amplifies the reductions in microcirculation in AD models64,65 and possibly in AD. Thus, aberrant angiogenesis has an amyloidogenic effect at the BBB66 and could represent an important novel target in AD.

Recent studies have also shown that the expression of two transcription factors which control vascular smooth muscle cells (VSMC) differentiation, the serum response factor (SRF) and myocardin (MYOCD), is increased in AD resulting in a hypercontractile phenotype in small cerebral arteries associated with brain hypoperfusion and diminished CBF responses to brain activation.67 These events may also contribute to the hypoperfusion observed in AD brains. Thus, drugs that specifically disrupt SRF-MYOCD interaction in small brain vessels may hold potential to improve brain perfusion and CBF dysregulation in AD.


Recent clinical observations provide strong evidence for the link between cerebrovascular disease and AD and/or cerebrovascular disease and cognitive decline. Here, we have briefly reviewed changes in the expression of key vascular receptors and genes in brain capillaries and small cerebral arteries in AD and in AD models that may lead to focal vascular and brain accumulations of Aβ, reductions in the resting CBF, attenuated CBF responses to brain activation and focal neuroinflammatory response. The activation of the neurovascular pathogenic pathway may, in turn, compromise synaptic and neuronal functions ultimately leading to neuronal damage with accumulation of intraneuronal tangles, neuronal loss and dementia. The early molecular changes within the neurovascular pathway may offer new therapeutic targets for controlling progression of dementia in AD, including therapies based on receptors RAGE and LRP and/or on genes implicated in the neurovascular AD model, such as MEOX2 and SRF/MYOCD.


The author thanks the National Institutes of Health (grants R37 AG023084 and R37 NS34467) and the Zilkha family for supporting his research. The author also wishes to thank Dr. Abhay Sagare for his help in preparing the figures, and Dr. Eleanor Carson-Walter for careful reading of the manuscript.


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