Alzheimer’s disease amyloid beta and prion protein amyloidogenic peptides promote macrophage survival, DNA synthesis and enhanced proliferative response to CSF-1 (M-CSF)

Abstract

Microglial cells, macrophage-lineage cells in the brain, are increased in amyloid-containing plaques in Alzheimer’s disease (AD) and in the lesions of prion diseases. Recent studies suggest that microglia have a central role in turnover of amyloid in these diseases. We report here that synthetic amyloid beta (Aβ) 1-42 and prion protein (PrP) 106-126 peptides promote macrophage survival; they also induce macrophage DNA synthesis, particularly in the presence of sub-optimal concentrations of the growth factor, macrophage-colony stimulating factor (M-CSF or CSF-1). These responses are proposed to provide a means to increase brain microglia/macrophage numbers thereby enhancing subsequent inflammatory/immune responses. These fibrillogenic peptides join the list of aggregates having these effects on macrophages, indicating the generality of this type of response.

Introduction

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by the presence of numerous amyloid plaques and neurofibrillary tangles. The plaques and cerebral neuropil feature reactive microglia; the major component of plaques is the Aβ peptide, a fragment of a larger, membrane spanning glycoprotein, the amyloid precursor protein. The predominant forms of Aβ in AD lesions are fragments at residues 42 or 40. There is substantial evidence that progressive cerebral accumulation of Aβ is an early and perhaps necessary feature of the sporadic forms of AD. One pathway of Aβ-induced neuron damage may involve inflammatory cells such as macrophages and reactive microglia. The latter cells are associated with most types of amyloid deposition and are increased in regions around compact amyloid deposits where they surround and infiltrate into the Aβ plaques [36]. The functions of this macrophage-lineage cell in AD are not known, although they have been considered as plaque-attacking scavenger cells, as sources of cytokines and other inflammatory mediators, and even as producers of Aβ [12]. Conversely, these cells may mediate the degradation and clearance of Aβ from the extracellular space. This pathway may underlie the beneficial effects of immunization in experimental models of Aβ cerebral deposition [31].

Associated with the transmissable spongiform encephalopathies (prion diseases) is the conversion of a normal cellular glycoprotein, the prion protein (PrP^c), to an abnormal isoform, the scrapie isoform (PrP^Sc), which shows increased protease resistance and insolubility and which accumulates in affected individuals, often in the form of extracellular amyloid deposits [29]. In addition to these properties shared with Aβ, PrP^Sc likewise has a high tendency to aggregate into fibrils [29]. PrP 106-126, a synthetic peptide corresponding to amino acid residues 106–126 of human PrP, is used as a model of prion protein neurotoxicity, forms amyloid-like fibrils in vitro, and can cause microglial cell activation and proliferation [5].

There are mouse data indicating that adult brain macrophages and a subpopulation of microglial cells are of bone marrow origin [8]. Macrophage-colony stimulating factor (M-CSF or CSF-1) is an important regulator of macrophage lineage development and function throughout the body [4]. There are in vivo and in vitro data showing that CSF-1 is important for normal microglial development as well as having a role in the cascade of events which surround the neurodegeneration in AD [1], [9], [11], [24], [39]. Macrophages are widely used as a model to study microglial activation by the amyloidogenic fragments of APP and PrP (see for example Ref. [6]). Involvement of scavenger receptors has been suggested for Aβ microaggregate uptake [26]. The engorgement of microglia with undigested Aβ is strikingly similar to the conversion of macrophages into foam cells when excessive amounts of cholesterol are taken up and stored as cholesterol ester droplets [25].

We have recently found that poorly degraded particulates, such as oxidized LDL, acetylated LDL, certain adjuvants (for example, alum) and arthritogenic crystals, promoted macrophage survival and DNA synthesis, and also allowed the loaded cells to proliferate strongly to low doses of CSF-1 [13], [14], [15], [16]. Given the increasingly important role of microglia/macrophages in amyloid turnover and clearance in neurodegenerative diseases, we sought to determine whether Aβ and PrP would behave similarly to these particulates.