Blood-derived plasminogen drives brain inflammation and plaque deposition in a mouse model of Alzheimer’s disease

Abstract

Two of the most predominant features of the Alzheimer’s disease (AD) brain are deposition of β-amyloid (Aβ) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of Aβ. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain’s immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.

The Plasma Amyloid Beta 42 (Aβ42) and Proteomics Profile Related to Canine Cognitive Dysfunction Syndrome (CCDS) in Thailand

“…Aβ plays a role not only in in ammation but also in the coagulation cascade. There is an association between haemostatic factors and in ammatory mechanisms in AD [37]. In our study, we found an increase in plasminogen, brinogen and kininogen.…”

“…In our study, we found an increase in plasminogen, brinogen and kininogen. In AD, plasminogen was found to colocalize with Aβ plaques [37], while brinogen was capable of enhancing Aβ aggregation and brillization, causing impairment in AD [48,49]. Patients with higher levels of plasma brinogen and plasminogen modulating neuroin ammation had worsening cognitive decline and Aβ deposition [37,50,51].…”

“…Proteomics is one of the most signi cant techniques that allows an extended investigation of neurodegenerative diseases. A blood-based proteomics approach was used extensively in humans with AD to study potential biomarkers or mechanisms related to this disease [36][37][38]. Proteomics in AD revealed many interesting proteins or pathways from CSF and blood, such as fatty acid oxidation and the advanced glycation end products/receptors for advanced glycation end products (AGE/RAGE) pathway [39,40].…”

Cerebrospinal Fluid Proteomic Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction

“…Likewise, coagulation factor V, a central mediator of hemostasis, has been previously linked to delirium pathogenesis [33]. Further, plasminogen has been shown to potentiate neuroin ammation [86,87] and Alzheimer's disease-related pathology [86], and elevated serum kininogen has been associated with depression [85]. As with complement, our data suggest a relationship between POCD and dysregulation of these in ammatory and thromboactive factors.…”

NLRC3 delays the progression of AD in APP/PS1 mice via inhibiting PI3K activation

“…There are two mechanisms related to the pathological process of AD: Aβ aggregation and activation of glial cells 11,12 . However, the causal relationship between the two needs to be further confirmed.…”