Matrix Metalloproteinases in Alzheimer's Disease and Concurrent Cerebral Microbleeds

Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer's disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral micro-bleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β(1-42) (Aβ42), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p <  0.05), and higher CSF MMP10 levels compared to controls (p <  0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p <  0.05), and CSF MMP10 with tau (St.B 0.38, p <  0.001) and p-tau (St.B 0.40, p <  0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients.