Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains

Abstract

β-Amyloid(1-42) (Aβ42), a major component of amyloid plaques, accumulates within pyramidal neurons in the brains of individuals with Alzheimer’s disease (AD) and Down syndrome. In brain areas exhibiting AD pathology, Aβ42-immunopositive material is observed in astrocytes. In the present study, single- and double-label immunohistochemistry were used to reveal the origin and fate of this material in astrocytes. Our findings suggest that astrocytes throughout the entorhinal cortex of AD patients gradually accumulate Aβ42-positive material and that the amount of this material correlates positively with the extent of local AD pathology. Aβ42-positive material within astrocytes appears to be of neuronal origin, most likely accumulated via phagocytosis of local degenerated dendrites and synapses, especially in the cortical molecular layer. The co-localization of neuron-specific proteins, alpha7 nicotinic acetylcholine receptor and choline acetyltransferase, in Aβ42-burdened, activated astrocytes supports this possibility. Our results also suggest that some astrocytes containing Aβ42-positive deposits undergo lysis, resulting in the formation of astrocyte-derived amyloid plaques in the cortical molecular layer in brain regions showing moderate to advanced AD pathology. These astrocytic plaques can be distinguished from those arising from neuronal lysis by virtue of their smaller size, their nearly exclusive localization in the subpial portion of the molecular layer of the cerebrocortex, and by their intense glial fibrillary acidic protein immunoreactivity. Overall, Aβ42 accumulation and the selective lysis of Aβ42-burdened neurons and astrocytes appear to make a major contribution to the observed amyloid plaques in AD brains.

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to profound memory loss, cognitive decline, and preferential loss of cholinergic and cholinoceptive neurons in the cerebral cortex and hippocampus [45]. Telltale pathological features include an abundance of focal, extracellular deposits of amyloid (amyloid plaques) and neurofibrillary tangles [20], [46], [54], [61]. A principal component of amyloid plaques is amyloid β(1-42) (Aβ42), a peptide fragment composed of 42 amino acid residues derived from a selective proteolytic cleavage of the amyloid precursor protein by the sequential actions of beta- and gamma-secretases [10], [21], [27], [31], [46], [47], [50]. Increased amyloid deposition in the brain and neurodegeneration have been linked to overproduction of the amyloid precursor protein and Aβ42 in early onset familial AD cases [21], [27], [38], [49], [61], [64] caused by mutations in the presenilin genes [42] that have been recapitulated partially in transgenic mice [20], [29], [32]. Despite an extensive literature documenting amyloid deposition within the brain, a clear causal relationship between the increased deposition of Aβ42 and AD has yet to be defined. Recently, however, Aβ42 has been shown to accumulate within neurons prior to the appearance of amyloid plaques in AD brains as well as in the brains of Down syndrome patients [11], [22], [25], [57], [58], [60]. The recent demonstration that Aβ42 accumulation occurs selectively in neurons that abundantly express the alpha7 nicotinic acetylcholine receptor (α7nAChR) and that these cells can undergo lysis leading to plaque formation when their Aβ42 content becomes excessive provides an alternative pathway for the origin of amyloid plaques in AD brains [11], [34].

Aβ42 has also been detected within astrocytes surrounding both neuritic and diffuse amyloid plaques as well as in cultured glial cells [1], [19], [37], [48], [63], [65]. These cells are often activated in response to neuropathological insults, giving rise to a series of changes that are collectively referred to as astrogliosis [16], [18], [23], [26], [44]. A widely used indicator of astrocyte activation is the dramatically increased expression of glial fibrillary acidic protein (GFAP) [16]. In AD brains, astrocytes in the cortical molecular layer as well as those closely associated with amyloid plaques in the underlying pyramidal cell layers accumulate Aβ42 intracellularly [19], [52], [53]. In the latter case, astrocytes are generally found just outside the plaque boundary, where they envelop the amyloid deposits with thick cytoplasmic processes and extend thin branches deep into the plaque interior [1], [2], [19], [53], [62], [63]. Although activated astrocytes can accumulate Aβ42 in AD brains, the source(s) of the Aβ42 and mechanisms of its accumulation are unknown. In the present study, we have used single- and double-label immunohistochemistry to investigate the origin, distribution and fate of Aβ42-positive material in activated astrocytes within the entorhinal cortex of AD brains. Overall results suggest that (1) the accumulation of Aβ42 in astrocytes is a consequence of the enhanced phagocytic activity of these cells, through which neuronal debris containing Aβ42 is internalized and (2), like neurons, Aβ42-burdened astrocytes can undergo lysis and give rise to astrocytic plaques.