Alzheimer's Disease: Another Target for Heparin Therapy

Abstract

Alzheimer's disease (AD) is the leading cause of dementia and cognitive decline in the elderly. Brain tissue changes indicate that the two main proteins involved in AD are amyloid-β(A-β), which is associated with the formation of senile amyloid plaques, and tau, which is associated with the formation of neurofibrillary tangles. Although a central role for A-β in the pathogenesis of AD is indisputable, considerable evidence indicates that A-β production is not the sole culprit in AD pathology. AD is also accompanied by an inflammatory response that contributes to irreversible changes in neuronal viability and brain function, and accumulating evidence supports the pivotal role of complement and contact systems in its pathogenesis and progression. The complexity of AD pathology provides numerous potential targets for therapeutic interventions. Compounds that interact directly with A-β protein or interfere with its production and/or aggregation can reduce the inflammatory and neurotoxic effects of A-β, and heparin, a glycosaminoglycan mixture currently used in the prophylaxis and treatment of thrombosis, might be a candidate, as recent research has been extended to consider its nonanticoagulant properties, including its modulation of various proteases and anti-inflammatory activity.

Histological and Direct Evidence for the Role of Complement in the Neuroinflammation of AD

“…However, in in vitro and in animal studies the use of compounds targeting C3 activation, such as VCP [241], and blocking C5a-CD88 interactions (PMX205 [243]) had favourable effects in AD mouse models. Also low molecular weight heparin enoxparin, that can potentiate the functional activity of C1-Inh and can also interfere with A -C1q interactions, reduced C activation, glial cell activation and amyloid load in an AD mouse model [56,234]. These results suggest that targetting C activation can potentially retard or prevent AD related pathological changes.…”

“…vivo [56,234]. These findings suggest that heparin analogues may be interesting therapeutics for AD.…”

“…The low molecular weight heparin enoxparin was shown to potentiate C1-Inh functioning and to reduce the ability of A to activate complement and contact systems, two powerful effectors of inflammatory response in AD brain [234]. Heparin can bind to A (HHQK) and prevent A aggregation and C activation through interference with C1q binding [56]. In vitro, enoxaparin inhibited the pro-inflammatory and neurotoxic effects of A , and in mouse studies, long-term prophylactic treatment with enoxaparin reduced the numbers of activated astrocytes and amyloid load in an AD model (APP23 mice) in Fig.…”

“…Inh (see for reviews [52,56]). The type and degree of Creg expression can, however, also direct the C mediated response.…”

CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer’s Disease

“…In addition to the anti-inflammation role, CFH acts as an extracellular matrix component and interacts with a wide selection of ligands (Ferreira et al, 2010), such as the C-reactive protein (CRP) (Strang et al, 2012), heparin (Bergamaschini et al, 2009), zinc (Suh et al, 2000), and sialic acid (Patel et al, 2006). All these ligands may be involved in the accumulation of senile plaque in the AD brain.…”