Neurovascular mechanisms of Alzheimer's neurodegeneration

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In contrast to traditional neuroncentric views of Alzheimer's disease (AD), recent findings indicate that neurovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Here, I propose the neurovascular hypothesis of AD, suggesting that faulty clearance of amyloid β peptide (Aβ) across the blood–brain barrier (BBB), aberrant angiogenesis and senescence of the cerebrovascular system could initiate neurovascular uncoupling, vessel regression, brain hypoperfusion and neurovascular inflammation. Ultimately, this would lead to BBB compromise, to chemical imbalance in the neuronal environment and to synaptic and neuronal dysfunction, injury and loss. Based on the neurovascular hypothesis, I suggest an array of new potential therapeutic approaches that could be developed for AD, to enhance Aβ clearance and neurovascular repair, and to protect the neurovascular unit from divergent inducers of injury and apoptosis.

Introduction

Alzheimer's disease (AD) is the major cause of dementia with advancing age. Since the first description of neuronal and vascular lesions in this heterogeneous disorder by Alzheimer [1], there has been little clarity how these lesions relate to each other and contribute to a chronic neurodegenerative condition. Mild cognitive impairment (MCI), defined as memory deficits with preservation of other cognitive and functional brain activities, is the initial clinical stage of the disease [2]. Whether the MCI results from neuronal loss within circuit-specific pathways involved in learning and memory [3] and/or from cerebrovascular dysregulation within these pathways [4], and whether finding the cure for MCI would delay or cure AD, remain debatable.

AD is characterized by elevated levels of amyloid β peptide (Aβ) in the brain that are associated with neuronal toxicity 5, 6 and vascular toxicity 7, 8. Neurofibrillary tangles and senile plaques are degenerative cellular changes necessary for the neuropathological diagnosis of AD [9]. Their specificity for AD has been questioned because diffuse plaques are found in neurologically normal aged humans, and these lesions can also be induced by hypertension [10]. However, the distribution of such tangles and plaques in AD reflects preferential disruption of hippocampal entorhinodendate and corticocortical association pathways [9].

Recent emphasis on co-morbidity of AD and cerebrovascular disease 11, 12, the link between AD and atherosclerosis 13, 14, 15, cognitive impairment associated with amyloid angiopathy 16, 17, significant cerebral microvascular pathology 10, 18 and deficient clearance of Aβ across the blood–brain barrier (BBB) in AD 6, 19, 20, 21 all indicate that vascular disorder is an important feature of chronic neurodegeneration condition in AD (Box 1). Therefore, neurovascular dysfunction could have a major role in the pathogenesis of AD.

Section snippets

Neurovascular unit

The neurovascular unit (Figure 1) maintains tight control of the chemical composition of neuronal internal environment by regulating local cerebral blood flow (CBF) and molecular transport across the BBB.

BBB Aβ transport pathways

Transport exchanges across the BBB crucially influence the concentration of soluble Aβ in the CNS [19], which is central to formation of neurotoxic oligomeric Aβ species [5] and vasculotoxic aggregated forms of Aβ [8]. Physiological concentration of free Aβ in brain ISF is about sixfold greater than in plasma 38, 39, but the amount of free Aβ in extracellular body fluids including plasma is tenfold greater than in brain fluids, the ISF and CSF [19]. Increased basal Aβ levels in plasma have been

Insufficient angiogenesis and vascular regression

Neurovasculature is continuously modified during aging and neurodegenerative disorders such as stroke, vascular dementia and cerebral autosomal-dominant arteriopathy with sub-cortical infarcts and leucoencephalopathy (CADASIL) [52]. In certain brain regions, a pool of BEC can provide neuronal precursor cells [53]. BEC-mediated formation of capillaries is greatly reduced in the Tg2576 mouse model of AD [7], and high concentrations of Aβ that is rich in β-sheets is anti-angiogenic [8]. In AD,

Senescent cerebrovascular hypoperfusion

Senescent cells display permanent growth arrest, enlarged and flattened cytoplasm, and expression of senescence-associated β-galactosidase activity [54]. The senescent state is extremely stable, but numerous cellular functions are lost or diminished. Senescent cells accumulate during aging in different organs (e.g. skin, kidney and liver) 54, 55; endothelial senescence is a common feature of vascular aging and is accelerated by atherosclerosis, diabetes and coronary disease [55]. BEC derived

Neurovascular hypothesis

Dysfunction of the neurovascular unit suggests manifold neurovascular pathogenic cascades for AD (Figure 2). Faulty clearance of Aβ across the BBB, due to either aberrant angiogenesis [52] or endothelial senescence [55] associated with low levels of Aβ clearance receptors (e.g. LRP) 21, 45 or increased levels of its influx receptors (e.g. RAGE) [30], could increase concentrations of soluble neurotoxic Aβ in brain ISF and lead to formation of vascular amyloid lesions and elevated fibrillar Aβ

Therapies for AD based on neurovascular model

The currently prevailing concept states that deficient Aβ clearance is of major importance for late-onset, non-genetic AD (i.e. >98% of AD cases) 5, 6, 19, 49, 57. Therapies based on Aβ clearance have shown remarkable results in preclinical immunization trials [58] but have been less conclusive in humans [59]. However, the recognition of Aβ clearance pathways opens new therapeutic Aβ-lowering opportunities, including: activation of Aβ-degrading enzymes 48, 49; activation of astrocytes 50, 51;

Concluding remarks

The proposed neurovascular hypothesis challenges traditional neuroncentric view of AD. I suggest that identifying neurovascular pathogenic mechanisms should result in discovery of new therapeutic targets to control the progression, and/or delay the onset, of neurodegenerative disorder in AD by stabilizing and/or correcting the altered functions of the neurovascular unit that are associated with Aβ elimination, neurovascular repair and cellular protection.

Acknowledgements

My work on Alzheimer's disease and neurovascular protection was supported by the US Public Health service (grants AG023084, NS34467 and HL63290).

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