GM6 attenuates Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Aβ, p-tau and inflammation.

Abstract

Alzheimer's disease (AD) is characterized by cerebral amyloid-b (Ab) deposition, vascular alterations, tau pathology, microglia activation, and inflammation. Vascular dysfunction and amyloid burden are independent and equal predictors of cognitive decline in the elderly, with an additive adverse effect on cognition. Fibrinogen, a blood coagulation protein, is deposited in the AD brain; co-localizes with amyloid plaques, pericyte loss, dystrophic neurites, and activated microglia; and its increased concentrations in plasma and cerebrospinal fluid correlate with brain atrophy in AD patients. GM6 is a derivative of motoneuronotrophic factor (MNTF) which functions as a regulator of key biomarkers and acts upon multiple extracellular receptors to modulate a series of signaling pathways. This study evaluates the effects of GM6 on fibrinogen levels in two animal models of AD. APP and h-tau transgenic mice were treated with GM6 daily for up to 4 months and examined for changes in fibrinogen, Aβ peptide levels, plaques, inflammation, phosphorylated tau (p-tau) as well as behavioral changes associated with disease progression. Fibrinogen levels were determined by ELISA and western blot analysis. When we studied APP transgenic mice treated with GM6 compared to placebo, fibrinogen levels were significantly decreased (75%) along with diminished Aβ peptide levels, attenuation of plaque load, and a reduction in inflammatory biomarkers. In another study of the p-tau formation in the h-tau mice treated with GM6 compared to placebo, again a reduction in fibrinogen was observed along with reduction in p-tau and inflammation biomarker levels. In both transgenic mice, behavioral changes were attenuated with GM6 treatment. In both APP and h-tau mice, inflammation cytokines TNF-α, IL-1β, IL-6, and TGF-β were reduced by 80-90% as previously reported. In conclusion, to counter the additive adverse effect on cognition from vascular dysfunction and amyloid burden, GM6 may be a feasible approach to attenuate Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Ab, p-tau and inflammation.