The Amyloid-Tau-Neuroinflammation Axis in the Context of Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with the accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis has been associated with an active immune response and perivascular deposition of hyperphosphorylated tau. Despite the fact that in Alzheimer’s disease (AD) a major focus of research has been the understanding of the connection between parenchymal amyloid plaques, tau aggregates in the form of neurofibrillary tangles (NFTs), and immune activation, the contribution of tau and neuroinflammation to neurodegeneration associated with CAA remains understudied. In this review, we discussed the existing evidence regarding the amyloid diversity in CAA and its relation to tau pathology and immune response, as well as the possible contribution of molecular and cellular mechanisms, previously associated with parenchymal amyloid in AD and AD-related dementias, to the pathogenesis of CAA. The detailed understanding of the “amyloid-tau-neuroinflammation” axis in the context of CAA could open the opportunity to develop therapeutic interventions for dementias associated with CAA that are currently being proposed for AD and AD-related dementias.

A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy

“…As apolipoprotein-E (ApoE) is implicated in regulating vascular integrity, cholesterol transport, and immune responses, and ApoE 4 allele is the strongest genetic risk factor for both AD and CAA [ 68 – 72 ], we evaluated ApoE in Tg-FDD mice. The RNA-Seq analysis did not reveal changes in ApoE mRNA levels between WT and Tg-FDD mice.…”

“…For instance, changes in vascular components due to CNS injury have a direct influence on astrocyte signaling [ 85 ]. Astrocytes respond to and influence immune and inflammatory responses following insults such as excitotoxicity, ischemia, apoptosis, necrosis, and inflammatory cues by undergoing a pronounced transformative state called “reactive astrogliosis”, regulating inflammatory responses that can be either neuroprotective or neurotoxic and participating in migratory, phagocytic, and proteolytic activity [ 72 ]. The notion that the astrocyte and microglia phenotype observed in 9-month-old Tg-FDD results from a response to vascular amyloid deposits as opposed to overexpression of the mutant form of human BRI 2 is supported by the fact that the transgene expression is under the control of the mouse prion promoter, which is exclusively expressed in neurons [ 37 ].…”

“…New studies have demonstrated that several apolipoproteins, including ApoE, are TREM2 ligands, and that the APOE-TREM2 pathway plays a fundamental role in the microglial homeostatic signature [ 15 , 107 ]. However, the majority of TREM2 studies in AD relate to parenchymal amyloid deposition, and the role of TREM2 in vascular amyloid deposition and CAA is largely unknown [ 31 , 34 , 72 , 73 , 105 ]. Here, we demonstrated an increase in TREM2 mRNA levels in the Tg-FDD model in comparison with WT controls.…”

Vascular amyloid accumulation alters the gabaergic synapse and induces hyperactivity in a model of cerebral amyloid angiopathy

“…Although CAA is highly associated with the accumulation of Aβ (Attems, 2005), other types of amyloids associate with the vasculature. Therefore, CAA could be considered as a group of biochemically and genetically diverse disorders unified by amyloid accumulation in the arterial blood vessel walls (Cisternas et al, 2019). Two examples of non-Aβ CAA are Familial British dementia (FBD) and…”

“…Several studies have associated cerebrovascular pathologies with an increased risk for the development of AD and other dementias, indicating that the pathological mechanisms present during vascular disturbance contribute to the progression of the disease (Snyder et al, 2015). Cerebral amyloid angiopathy (CAA), typified by the cerebrovascular deposition of amyloid, is one of the most prevalent pathologies associated with AD (Cisternas, Taylor, & Lasagna‐Reeves, 2019). CAA is present in an estimated 70%–97% of individuals with AD (Attems, 2005) and directly increases with age.…”