Abstract
An impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer’s disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.
Highlights
Amyloid beta (Aβ) plaques with extracellular fibrillar deposits of amyloid β-peptide (Aβ) peptide and neurofibrillary tangles (NFTs) composed of phosphorylated tau represent the key histopathological hallmarks of Alzheimer’s disease [22, 33, 58].Aβ peptides are generated via sequential proteolytic cleavage of the amyloid precursor protein (APP) [47]
Aβ34 immunoreactivity is detected in brain capillaries of non-demented elderly individuals and this immunoreactivity is progressively reduced in Alzheimer’s disease (AD) patients In this study, we performed a comprehensive diseasestage dependent immunohistochemical analysis of Aβ34 immunoreactivity in hippocampal and cortical brain tissue from cognitively intact elderly individuals and AD patients of various Braak stages (Table 1)
Throughout disease stages, Aβ34 was predominantly found in small vessels, which were identified as brain capillaries based on their structure and diameter of < 10 um (Fig. 1a, Additional file 2a)
Summary
Amyloid beta (Aβ) plaques with extracellular fibrillar deposits of Aβ peptide and neurofibrillary tangles (NFTs) composed of phosphorylated tau represent the key histopathological hallmarks of Alzheimer’s disease [22, 33, 58].Aβ peptides are generated via sequential proteolytic cleavage of the amyloid precursor protein (APP) [47]. In addition to its role as the major β-secretase in APP processing, BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) has been shown to cleave longer Aβ isoforms at position 34 and this pathway has been identified as the major source of Aβ34 [19, 50]. This additional BACE1 mediated cleavage can only take place with Aβ peptides as substrates implying that BACE1 acts as an Aβ40/42 degrading enzyme to generate Aβ34 [19, 50]. We discovered a positive correlation between CSF Aβ34 levels and overall Aβ clearance rates in individuals with biomarker evidence of cerebral amyloid deposition [30]
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