Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis

Abstract

The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease (AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the ratio of AbetaDutch40/AbetaDutch42 toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.

Induction of cerebral β-amyloidosis: Intracerebral versus systemic Aβ inoculation

“…Total A␤ levels were determined on 10 -20% Novex Tricine Gels using Novex Tricine sample buffer including reducing agent (Invitrogen). To determine A␤40 and A␤42 levels, 10% bicineTris, 8 M urea SDS/PAGE was used as described previously (43). To measure A␤ concentrations on wires, the wires were heated in 100 L of sample buffer in a 1.5-mL microfuge tube at 95°C for 5 min.…”

“…The wires were either heated in PBS at 95°C for 10 min or plasma-sterilized before implantation. To do this, the wires were sealed in a STERRAD Tyvek pouch and sterilized in a STERRAD 100 S hydrogen peroxide gas plasma sterilizer (Advanced Sterilization Products) using the routine long cycle as programmed by the manufacturer (43). The wires were then implanted unilaterally into the hippocampus using a stereotaxic apparatus (AP, Ϫ2.5 mm; L, ϩ2.0 mm; DV, Ϫ1.8 mm).…”

Ischemic brain injury in cerebral amyloid angiopathy

“…An earlier theory suggested that A in CAA directly originates from smooth muscle cells in the vessel wall. 17,18 More recent models have suggested that A in CAA is predominantly generated by neurons [19][20][21] and subsequently deposited in the vessel wall because of impairment in A clearance. Impaired A clearance may be caused by alterations in perivascular drainage pathways [22][23][24] and deficits in endothelial-mediated active transport of A into the blood.…”

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

“…23). Previous studies have established the ratio of Aβ40 to Aβ42 as an important factor in determining the fibrillogenesis, toxicity and pathological distribution of Aβ in vivo [58][59][60] . The ability to obtain monomeric and protofibril preparations of Aβ42 and Aβ40 by SEC allowed us to characterize the interactions between these two peptides at the levels of monomers, protofibrils and fibrils.…”