The contact activation system and vascular factors as alternative targets for Alzheimer's disease therapy

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting millions of people worldwide. Extracellular beta‐amyloid (Aβ) plaques and neurofibrillary tau tangles are classical hallmarks of AD pathology and thus are the prime targets for AD therapeutics. However, approaches to slow or stop AD progression and dementia by reducing Aβ production, neutralizing toxic Aβ aggregates, or inhibiting tau aggregation have been largely unsuccessful in clinical trials. The contribution of dysregulated vascular components and inflammation is evident in AD pathology. Vascular changes are detectable early in AD progression, so treatment of vascular defects along with anti‐Aβ/tau therapy could be a successful combination therapeutic strategy for this disease. Here, we explain how vascular dysfunction mechanistically contributes to thrombosis as well as inflammation and neurodegeneration in AD pathogenesis. This review provides evidence that addressing vascular dysfunction in people with AD could be a promising therapeutic strategy.

Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer’s Disease

“…This is already the case in individuals with mild cognitive impairment, who often develop AD [ 5 , 94 ]. When activation of the contact system was inhibited, AD pathology and cognitive impairment were alleviated [ 13 ].…”

“…Fibrin(ogen) has the potential to aggregate with Aß, forming degradation-resistant deposits of Aß-containing fibrin clots in brain vessels. These clots are thought to be causally related with vascular and BBB dysfunction in AD pathology [ 13 ]. Aß-induced FXII activation in the contact system also leads to the production of kallikrein and proinflammatory bradykinin [ 13 ].…”

“…These clots are thought to be causally related with vascular and BBB dysfunction in AD pathology [ 13 ]. Aß-induced FXII activation in the contact system also leads to the production of kallikrein and proinflammatory bradykinin [ 13 ]. Kallikrein is thought to favor hemorrhagic conditions, which can enhance the risk of cerebral bleeding.…”

“…In this context, anticoagulants could be promising therapeutic candidates for targeting hemostatic and cerebrovascular dysfunctions and associated neurodegenerative processes in AD [ 9 , 10 , 11 ]. After first clinical evaluation more than 50 years ago, the renaissance of an anticoagulative therapy has been inspired by recent research that indicates that cerebrovascular damage and dysregulated intrinsic coagulation, as well as risk factors for cardiovascular disease, play important roles in AD pathogenesis [ 9 , 12 , 13 ]. Recently, quantitative transcriptome profiling of major vascular and perivascular cell types from hippocampal and cortical brain samples of individuals with AD has also indicated dysregulation of blood flow [ 14 ].…”

Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer’s Disease: A Narrative Review

“…Of particular interest are the peripheral proinflammatory cytokines (interleukin (IL)-IL-1β, IL-6 and tumor necrosis factor (TNF)-α) observed in the peripheral blood and autopsy samples of patients with mild to moderate late onset of AD [10][11][12]. The pathologic hallmarks of AD are the presence of amyloid plaques, which consist primarily of a small peptide termed amyloid-β, and neurofibrillary tau tangles which have been used as a therapeutic target in drug development, although with limited success in clinical trials [13]. On the other hand, modest rates of brain atrophy are common in the elderly, due to normal aging; conversely, intermediate atrophy is observed in patients with MCI and also those with AD, who suffer from accelerated brain atrophy [14,15].…”