Neuroserpin Binds Aβ and Is a Neuroprotective Component of Amyloid Plaques in Alzheimer Disease

Abstract

Alzheimer disease is characterized by extracellular plaques composed of A␤ peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the A␤ 1-42 peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasminogen activator and blocks the loop-sheet polymerization process that is characteristic of members of the serpin superfamily. In contrast neuroserpin accelerates the aggregation of A␤ 1-42 with the resulting species having an appearance that is distinct from the mature amyloid fibril. Neuroserpin reduces the cytotoxicity of A␤ 1-42 when assessed using standard cell assays, and the interaction has been confirmed in vivo in novel Drosophila models of disease. Taken together, these data show that neuroserpin interacts with A␤ 1-42 to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease.Alzheimer disease is the most common form of dementia. The pathological features are characterized by neurofibrillary tangles and extracellular A␤ plaques. The plaques are composed of 42 (A␤ 1-42 )-and to a lesser extent 40 (A␤ 1-40 )-amino acid fragments of the amyloid precursor protein (1). Overproduction of the more aggregatory A␤ 1-42 peptide is believed to cause neuronal dysfunction and death in most sporadic and familial forms of Alzheimer disease. Although insoluble plaques of A␤ 1-42 are a classic feature of the brains of patients with Alzheimer disease, these plaques are also present in some healthy, elderly individuals (2). This discrepancy, and the observation that soluble A␤ is a better marker of cognitive decline (3), has led to the proposal that mature amyloid plaques are an end stage aggregation product and that the directly neurotoxic species occur earlier in the aggregation pathway (4, 5). The description of soluble oligomers of A␤ that can cause neuronal dysfunction and death (4 -6) has emphasized the importance of understanding the pathways and kinetics of A␤ aggregation. The presence of ancillary proteins that interact with A␤ may stabilize particular aggregation intermediates or seed-specific patterns of aggregation that have distinct toxic properties. Of particular interest in this regard are several proteins that are associated with ␤ amyloid plaques such as apolipoprotein E (7) and the serine protease inhibitor (serpin) ␣ 1 -antichymotrypsin (8). The role of these proteins is underscored by the finding that the E4 polymorphism of apolipoprotein E is the most powerful genetic risk factor for the development of sporadic Alzheimer disease (9, 10), most likely because it accelerates the deposition of A␤ in the brain (11-13). ␣ 1 -Antichymotrypsin is also found in the majority of senile plaques (8), with cerebrospinal fluid concentrations being consistently raised in patients with Alzheimer disease (14). Depending on the relative molar ratio, ␣ 1 -antichymotrypsin may accelerate or inhibit the aggregation of the A␤ peptide in vitro (15,16).We h...

Amyloid-β Peptide (Aβ) Neurotoxicity Is Modulated by the Rate of Peptide Aggregation: Aβ Dimers and Trimers Correlate with Neurotoxicity

“…Indeed, elements that are associated with the plaques such as zinc and neuroserpin are known to accelerate the aggregation of A␤ peptides and have been shown to inhibit A␤ toxicity (Cuajungco et al, 2000;Kinghorn et al, 2006). Results seen here are also consistent with those seen by Cheng et al (2007) in which transgenic mice carrying the A␤ arctic mutation, which has the propensity to increase A␤ fibrillization, had normal neurological functions, although there was an increase in plaque load (Cheng et al, 2007).…”

BRICHOS Domains Efficiently Delay Fibrillation of Amyloid β-Peptide

“…HAT belongs to the serpin family, other members of which have been reported to affect A␤ aggregation (52,53). Egg white cystatin C has about the same molecular mass as the BRICHOS domain, and scMN-2 was chosen because it has the same net charge (Ϫ2) as pro-SP-C BRICHOS to mimic any nonspecific protein effect.…”

LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye

“…Pitting indicates defects in the lens material secreted by cone cells, and suggests defects in cone cells structure or function. Mutant retinas occasionally had small black spots in the center of the eye, suggesting cell death (18). lkb1 4B1-11 eyes were intermediate in size between lkb1 4A4-2 and wild-type retinas, and defects in ommatidial and bristle organization were less severe than lkb1 4A4-2 retinas [compare Fig.…”