Review: Cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy

Abstract

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aβ), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aβ (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

4D flow MRI for intracranial hemodynamics assessment in Alzheimer’s disease

“…5,29 Studies suggest vascular pulsation is the motive force for perivascular drainage of soluble metabolites. 30 As arteries age they become stiffer, implying a reduction in the amplitude of vascular pulsations.…”

“…This failure to dispose of soluble metabolites from the brain may have important implications for the pathogenesis of dementia. [5][6][7][8] Consequently, there is interest in noninvasive methods to assess cerebrovascular hemodynamics as potential systemic indicators of AD. 9 One common approach for the probing of intracranial hemodynamic parameters is the use of Transcranial Doppler ultrasound (TCD), which has been used successfully in other hemodynamic studies.…”

APOE ɛ2 is associated with white matter hyperintensity volume in CADASIL

“…11 Although vascular A deposition has no role in CADASIL, APOE "2 may be associated with impaired drainage of other proteins leading to microvascular damage. 12 Furthermore, the "2 allele is associated with specific vessel pathologies in CAA, such as vessel dilation, fibrinoid necrosis, microaneurysms and double barreling. 13 Some of these vasculopathic changes have also been observed in CADASIL.…”

Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase

“…[8][9][10][11] Alzheimer disease is one of neurodegenerative diseases, but vascular pathology contributes to Alzheimer disease changes to variable degrees. [30][31][32][33][34] There is an emerging concept of protein elimination failure arteriopathy 35 where waste products such as amyloid-β accumulate in the brain as a result of cerebral perfusion failure and evoke disparate brain disorders because perivascular drainage of waste products are driven by arterial pulsation. 36 Because reduced amyloid-β clearance from the brain seems to be mainly responsible for the pathogenesis of sporadic Alzheimer disease, 37 the drainage of extracellular amyloid-β along the arteries seems to be a significant strategy for removal of amyloid-β from the brain.…”