Alzheimer's disease β‐secretase BACE1 is not a neuron‐specific enzyme

Abstract

The brains of Alzheimer's disease (AD) patients are morphologically characterized by neurofibrillar abnormalities and by parenchymal and cerebrovascular deposits of b-amyloid peptides. The generation of b-amyloid peptides by proteolytical processing of the amyloid precursor protein (APP) requires the enzymatic activity of the b-site APP cleaving enzyme 1 (BACE1). The expression of this enzyme has been localized to the brain, in particular to neurons, indicating that neurons are the major source of b-amyloid peptides in brain. Astrocytes, on the contrary, are known to be important for b-amyloid clearance and degradation, for providing trophic support to neurons, and for forming a protective barrier between b-amyloid deposits and neurons. However, under certain conditions related to chronic stress, the role of astrocytes may not be beneficial. Here we present evidence demonstrating that astrocytes are an alternative source of BACE1 and therefore may contribute to b-amyloid plaque formation. While resting astroyctes in brain do not express BACE1 at detectable levels, cultured astrocytes display BACE1 promoter activity and express BACE1 mRNA and enzymatically active BACE1 protein. Additionally, in animal models of chronic gliosis and in brains of AD patients, there is BACE1 expression in reactive astrocytes. This would suggest that the mechanism for astrocyte activation plays a role in the development of AD and that therapeutic strategies that target astrocyte activation in brain may be beneficial for the treatment of AD. Also, there are differences in responses to chronic versus acute stress, suggesting that one consequence of chronic stress is an incremental shift to different phenotypic cellular states.

Alzheimer's Factors in Ischemic Brain Injury

“…-amyloid peptide within astrocytes appears to be of blood origin, possibly deposited by phagocytosis of locally opened blood-brain barrier (Pluta et al, 1996). In contrast, current results suggest that astrocytes could also act as a source for -amyloid peptide, because they overexpress -secretase in response to long-term pathology (Rossner et al, 2005). Although it remains unclear to which degree astrocytes contribute to -amyloid peptide synthesis or its clearance, it seems apparent that astrocytes contribute to neuroinflammation cascades.…”

Astrocytes in Alzheimer's Disease

“…184,185 Various brain insults that triggered astrogliosis (e.g., immunolesion of cholinergic septohippocampal afferents or occlusion of middle cerebral artery) also triggered astrocytic expression of BACE 1. 178 Similarly, increased APP production was detected in the rat model of chronic neocortical astrogliosis, induced by grafting foetal cortical tissue in the midbrain of neonatal animals; chronically activated astrocytes were immunostained for APP as well as for another AD-related marker apolipoprotein E. 186 The neurovascular unit in AD: role for astrocytes Vascular impairments represent an important factor in the pathology of AD. Numerous imaging studies of humans have found that significant reduction in blood flow in the brains of patients with AD and AD-like status indicated the role for vascular defects at the early stages of the disease (see References [187][188][189] for comprehensive review).…”

“…In conditions of ADlike pathology or even under chronic stress, astrocytes start to express BACE 1, thus acquiring A␤Ϫproducing ability. 178 Astroglial BACE 1 was detected in activated astrocytes surrounding A␤ plaques in several transgenic AD mice models, such as Tg2576 183 and double mutated K670N-M671L APP. 184,185 Various brain insults that triggered astrogliosis (e.g., immunolesion of cholinergic septohippocampal afferents or occlusion of middle cerebral artery) also triggered astrocytic expression of BACE 1.…”

Astrocyte signaling and neurodegeneration

“…74 However, in both autoptic AD cases and transgenic mice, BACE1 expression and Aβ deposits are not only restricted to neurons, but they co-localize also with astroglial markers. [77][78][79][80] This suggests that astrocytes may contribute to the generation of pathological protein aggregates in vivo. In keeping, recent studies in vitro confirmed that, under normal conditions, astrocytes possess the APP-processing machinery for generating Aβ peptide, i.e., APP itself, BACE1 and/or its close homolog BACE2.…”