α-1-Antichymotrypsin Promotes β-Sheet Amyloid Plaque Deposition in a Transgenic Mouse Model of Alzheimer's Disease

Abstract

␣ 1 -Antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid ␤-peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an agedependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/ amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid ␤-peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

“…Overexpression of human ACT accelerates amyloid pathology in human APP Tg mice (Mucke et al, 2000;Nilsson et al, 2001). Although ACT functions remain unclear and some reports about biochemical interactions with Ab are controversial, most evidence argues that ACT can play a causal role in amyloid aggregation and plaque formation, which is post-Abproduction (Ma et al, 1994).…”

“…ACT is an acute phase protein induced by inflammation (Akiyama et al, 2000) as well as a pro-amyloidogenic molecule (Mucke et al, 2000;Nilsson et al, 2001). In our experiments, the analysis of ACT was performed in human and mouse material rather than in the rat infusion model, because a rat homolog of ACT has not been adequately identified.…”

“…Amyloid pathology can be affected by multiple inflammation-driven pathways, notably those involving acute phase proteins. Inflammation-related astrocyte molecules like apolipoprotein E (apoE) (Bales et al, 1997) and a 1 -antichymotrypsin (ACT) (Mucke et al, 2000;Nilsson et al, 2001) regulate amyloid pathology in APP Tg mice. ACT is an acute phase protein that accelerates amyloid pathology in APP Tg mice and is elevated in AD (Abraham et al, 1988;Pasternack et al, 1989;Koo et al, 1991;Shoji et al, 1991;Licastro et al, 1998), where it accumulates with amyloid plaques.…”

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

“…Exclusively, neuronal expression of the APP transgenes with neuron-specific promoters resulted in plaques with a regional distribution and characteristic relationships with glia that strongly resemble AD [24,28,57] providing compelling evidence for a neuronal source of the A␤ in deposits. Manipulation of these models has also provided solid evidence that two of the astrocyte protein products, ApoE [4] and ␣1-ACT [45,49], play an important role in amyloid plaque deposition. Therefore, one must cede the point that astrocytes "contribute" to plaque formation or progression although there is also strong evidence for an astrocytic role in amyloid clearance [46,71].…”

CSF levels of PSA and PSA–ACT complexes in Alzheimer's disease

“…Although ACT is predominantly produced in the liver, it is also synthesized in the brain, mainly by astrocytes. 2 Studies in transgenic mouse models of AD revealed that ACT accelerates and enhances amyloid plaque formation, 3,4 which suggests a role for ACT in AD pathophysiology. Elevated levels of ACT are found in the brain, serum and cerebrospinal fluid (CSF) 5 -9 of AD patients and high ACT in plasma is associated with cognitive decline in elderly subjects.…”