Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the "vascular hypothesis", AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.

Keywords: Alzheimer’s disease; amyloid peptides; cerebrovascular disease; platelets; vascular cells.

Figure 1

Amyloidogenic and non-amyloidogenic pathways of APP. Amyloid precursor protein APP is a single pass transmembrane glycoprotein. APP may be cleaved by β−γ secretases (amyloidogenic) releasing amyloid Aβ peptide(s) or by α−γ secretases (non-amyloidogenic). The two pathways are mutually exclusive and are detailed in the text.

Figure 2

Cellular and histological effects of amyloid peptide β on the endothelium. Direct stimulation of the receptor for advanced glycation end products (RAGE) stimulates NADPH oxidases (NOXs), intracellular calcium increase and c-Jun N-terminal kinases (JNKs). The stimulation of NOXs and generation of reactive oxygen species (ROS) induce the activation of hypoxia-induced factor 1 (HIF) and NF-E2-related Factor 2 (Nrf2). Together with the activation of JNKs, the activity of these transcription factors leads to upregulation of pro-inflammatory genes, including cyclooxygenase 2 (COX2), metalloproteases (MMPs), interleukins 1β/6/8 (IL1β/6/8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor α (TNF α) and transforming growth factor beta (TGF-β). Additional effect of ROS increase are the reduction of nitric oxide (NO) bioavailability, which leads to pro-thrombotic endothelial cell phenotype, and apoptosis. The intracellular calcium increase leads to intimal loosening via zona occludens protein 1 (ZO-1). The accumulation of thrombin in the amyloid plaques further facilitates endothelial inflammation via stimulation of the protease-activated receptors (PARs).

Figure 3

Aβ peptides-induced platelet activation. Aβ peptides present in plasma activate platelets inducing activation of PLC/PKC and intracellular Ca²⁺ movement, granule secretion, kinase activation, rap1b mediated-integrin activation and aggregation. Aβ peptides released from α-granules, ADP released by dense granules, and formation of TxA₂ reinforce platelet activation. Aβ peptides also promotes ROS formation, caspase activation and membrane scrambling. Activated platelets recruit leukocytes and promotes vascular inflammation.