Abstract
BackgroundLoss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer’s disease (AD). The role of pericyte in early stage of AD pathogenesis remains unclear.MethodsWe investigated the dynamic changes of soluble platelet-derived growth factor receptor β (sPDGFRβ) in cerebrospinal fluid (CSF), a marker of brain pericyte injury, in transition from normal ageing to early AD in a cognitively unimpaired population aged 20 to 90 years. Association between sPDGFRβ and ATN biomarkers were analyzed.ResultsIn lifetime, CSF sPDGFRβ continually increased since age of 20 years, followed by the increases of phosphorylated tau-181 (P-tau181) and total tau (T-tau) at the age of 22.2 years and 31.7 years, respectively; CSF Aβ42 began to decline since the age of 39.6 years, indicating Aβ deposition. The natural trajectories of biomarkers suggest that pericyte injury is an early event during transition from normal status to AD, even earlier than Aβ deposition. In AD spectrum, CSF sPDGFRβ was elevated in preclinical stage 2 and participants with suspected non-AD pathophysiologies. Additionally, CSF sPDGFRβ was positively associated with P-tau181 and T-tau independently of Aβ42, and significantly strengthened the effects of Aβ42 on P-tau181, suggesting that pericyte injury accelerates Aβ-mediated tau hyperphosphorylation.ConclusionsOur results suggest that pericyte injury contributes to AD progression in the early stage in an Aβ-independent pathway. Recovery of pericyte function would be a target for prevention and early intervention of AD.
Highlights
Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer’s disease (AD)
The correlation between cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor β (sPDGFRβ) and age remained significant after adjusting for vascular risk factor (VRF) burden and APOE ε4 status (r = 0.411, p < 0.001), indicating that brain pericyte injury is likely to be an attribute of ageing
To investigate the roles of brain pericyte injury in AD progression, we investigated the natural trajectories and evolution sequence of CSF Aβ, tau and sPDGFRβ in lifetime
Summary
Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer’s disease (AD). Human studies revealed significant pericyte loss in the brain and elevated soluble platelet-derived growth factor receptor β (sPDGFRβ), a well-known marker of pericyte injury [14], in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and Alzheimer’s dementia, indicating a role of brain pericytes in AD pathogenesis [9, 15,16,17]. These studies only observed pericyte changes in symptomatic stages. We investigated the dynamic changes of CSF sPDGFRβ in the process of normal ageing and preclinical AD, and its correlation with Aβ and tau clearance across BBB
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