Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease

Abstract

Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

“…Our data are in agreement with previous findings demonstrating that the expression of TGF-␤1 in the brain parenchyma induces cerebrovascular and meningeal A␤ deposition at 12-18 months of age in TGF-␤1 transgenic mice (line T64 or T115) or at 2-3 months of age in hAPP/TGF-␤1 biogenic mice expressing the human APP and TGF-␤1 (line T64 or T115) (8). In addition to its proamyloidogenic effect, TGF-␤1 may exert a more complex role because 12-15-month-old hAPP/TGF-␤1 double transgenic mice (10) displayed plaque burden reduction associated with increased microglia activation and increased clearance of A␤ compared with hAPP mice.…”

“…The following primary antibodies were used: R7 (1:1,000) against KPI-APP proteins (17), R1736 (1:1,000) against sAPP-␣ (18), 192wt (1:500) against sAPP-␤ (19), FCA3340 (1:1,000) against human A␤40 (20), FCA3542 (1:1,000) against human A␤42, sc-146 (1:200) against human and murine TGF-␤1 (Santa Cruz Biotechnology Inc.), OX42 (1:100) against CD11b (kindly provided by Dr. Anna-Maria Planas), and anti-GFAP antibody (1:100) and M4403 (1:100) against actin (Sigma). R1742 and R600 were generated to synthetic A␤ [37][38][39][40][41][42] and A␤ [1][2][3][4][5][6][7][8][9][10] and tested against synthetic A␤ and A␤ …”

Amyloid β-Peptide Possesses a Transforming Growth Factor-β Activity

“…TGF-␤ has been shown to protect neurons from cell death (28 -32). Since TGF-␤ expression has been detected in Alzheimer's disease lesions (28,(33)(34)(35), we hypothesize that the TGF-␤ antagonist activity (TGF-␤ receptor binding inhibitory activity) of A␤-(1-40) monomers and aggregates may counteract this neuroprotective effect of TGF-␤. As both glial cells and monocytes have been shown to express TGF-␤ (35) and to respond to TGF-␤ stimulation (28), the partial TGF-␤ agonist activity (growth inhibition) of A␤ aggregates may also play an important role in the chemotaxis and activation of astrocytes and microglia that are associated with Alzheimer's disease.…”

“…High molecular mass protein standards (myosin, 205 kDa; ␤-galactosidase, 116 kDa; phosphorylase, 97 kDa; bovine serum albumin, 66 kDa), A␤-(1-40), A␤-(1-16), and A␤- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were obtained from Sigma. A␤-(1-40), A␤- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and A␤- (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) were obtained from Bachem Bioscience, Inc. (King of Prussia, PA). Disuccinimidyl suberate was obtained from Pierce.…”

A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

“…For example, targeted disruption of the TGF-␤1 gene in mice causes enhanced inflammatory responses leading to early death (9,10). Overexpression of brain-derived TGF-␤ promotes vascular amyloidogenesis, a histopathological hallmark of Alzheimer's disease (11,12). However, the molecular mechanisms that lead to these phenomena remain poorly understood.…”