Alzheimer disease and platelets: how's that relevant

Abstract

Alzheimer Disease (AD) is the most common neurodegenerative disorder worldwide, and account for 60% to 70% of all cases of progressive cognitive impairment in elderly patients. At the microscopic level distinctive features of AD are neurons and synapses degeneration, together with extensive amounts of senile plaques and neurofibrillars tangles. The degenerative process probably starts 20-30 years before the clinical onset of the disease. Senile plaques are composed of a central core of amyloid β peptide, Aβ, derived from the metabolism of the larger amyloid precursor protein, APP, which is expressed not only in the brain, but even in non neuronal tissues. More than 30 years ago, some studies reported that human platelets express APP and all the enzymatic activities necessary to process this protein through the same pathways described in the brain. Since then a large number of evidence has been accumulated to suggest that platelets may be a good peripheral model to study the metabolism of APP, and the pathophysiology of the onset of AD. In this review, we will summarize the current knowledge on the involvement of platelets in Alzheimer Disease. Although platelets are generally accepted as a suitable model for AD, the current scientific interest on this model is very high, because many concepts still remain debated and controversial. At the same time, however, these still unsolved divergences mirror a difficulty to establish constant parameters to better defined the role of platelets in AD.

Figure 1

Principal platelet membrane receptors and signal transduction pathways. Different receptors are stimulated by various agonists, almost converging in increasing intracellular Ca²⁺ concentration. Platelet activation induces an inside out signaling pathway that active α_IIbβ₃ integrin. The subsequently link of α_IIbβ₃ with fibrinogen lead to an outside in signaling pathway that promotes irreversible aggregation. Abbreviations: TXA2, tromboxane A2; THR, thrombin; PAR1, protease-activated receptor-1; VWF, Von Willebrand Factor; RGD, arginine, glycine, aspartic acid; GPIb-IX-V, glycoprotein Ib-IX-V; FcγRIIA, cristallizable fragment γ receptorIIA; α_IIbβ₃, α_IIbβ₃ integrin; cAMP, cyclic adenosin monophosphate; P2Y12, P2Y12 receptor; P2Y1, P2Y1 receptor; ADP, adenosin diphosphate; 5HT, 5-hydroxytryptamine; APP, amyloid precursor protein; GPVI, glicoprotein VI; α2β1, α2β1 integrin; Syk, Syk tyrosin kinase; PLCγ2, phospholipase γ2; DAG, diacilglicerol; PKC, protein kinase C; IP3, inositol 3-phosphate, Ca2+, calcium, PLA2, phspholipase A2; AA, arachidonic acid; COX, ciclooxigenase; PLCβ, Phospholipaseβ.

Figure 2

Abnormalities on AD platelets. Some membrane (secretases, phospholipases), cytosolic (monoamine oxidase, ciclooxigenases) and mithocondrial activities (nitric oxide synthase, sodium potassium ATPase pump) are compromised in AD platelets. Alterations are evident in the APP processing itself, membrane fluidity and cholesterol levels; in serotonin levels/uptake and intracellular Ca²⁺ levels; in nitric oxide and peroxynitrite production. Abbreviations: PLCδ, phospholipase C δ; β, β-secretase; α, α-secretase; γ-secretase complex; APP forms, amyloid precursor protein forms; CaM, calmodulin; chl, cholesterol; MAO-B, monoamino-oxidase B; PLA2, phosholipase A2; COX-1, ciclooxigenase-1, COX-2, ciclooxigenase-2; 5HT, 5-hydroxytryptamine; NOS, nitric oxide synthase; NO nitric oxide; O2^- superoxide anion; ONOO^- peroxynitrite; Na+/K + −ATPase, sodium potassium ATPase pump; Ca2+, calcium.