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

[cadasil]

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 .