The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation
Introduction
Alzheimer himself hinted at the possibility that Alzheimer’s disease pathology might involve an inflammatory reaction when he described reactive astrocytes and microglia in affected brain regions of his first patient [4]. However, the absence of standard features of inflammation such as swelling and lymphocyte infiltration argued against such a description. A change of view began to arise in the 1980’s when activated microglia in Alzheimer’s disease brain were found to express HLA antigens characteristic of inflammation [67] and when the Alzheimer amyloid deposits were found to contain, in addition to Aβ peptides, other proteins that are normally secreted during inflammation and its associated acute phase response (for reviews, see [15], [53]. For example, the inflammation/acute phase protein α1-antichymotrypsin (ACT) was found to be a structural component of the Alzheimer amyloid deposits, but not to be associated with the deposits in other amyloidoses [1], [3]. Furthermore, ACT mRNA and protein are undetectable in normal brain and are massively expressed in astrocytes in those parts of the AD brain, such as the hippocampus, that develop large numbers of amyloid plaques [1], [33], [56]. ACT is an inhibitor of chymotrypsin-like serine proteases and is normally produced in the liver as part of the body’s “acute phase response” to inflammation [77]. The finding that ACT is overexpressed in astrocytes in affected areas of the Alzheimer brain provided the first clear indication that inflammation and an acute phase response in the brain were part of the disease. The question that remained was whether inflammation was merely a response to the disease, or whether it was an essential cause.
In this paper, we will present both established and new evidence that implicates inflammation and the molecules it produces, particularly ACT, apoE, and IL-1, in Alzheimer amyloid formation. The conclusion is that Aβ does not function alone to cause Alzheimer’s disease, but must interact with one or more pathological chaperones that serve to catalyze the polymerization of Aβ into amyloid filaments. In the absence of inflammation and amyloid promoters, Aβ alone might be relatively harmless.
Section snippets
The role of ACT and apoE in Alzheimer amyloid formation
The findings that ACT binds directly to the Aβ peptide and is an integral component of the Alzheimer amyloid filaments, and that the mature amyloid deposits are restricted to the same brain regions in which ACT is overproduced, led us to propose that ACT contributes directly to amyloid formation [1], [59], [62]. When ACT is added to preparations of synthetic Aβ peptide in vitro, it promotes the polymerization of Aβ into amyloid filaments ([41]; Fig. 1) which are toxic to neurons in culture [42]
Are apoE and ACT amyloid promoters or amyloid inhibitors?
All of the pathological evidence (such as the overexpression of ACT and apoE in affected areas of AD brain and the increased amyloid load in apoE4 and ACT-A carriers) together with most of the biochemical evidence, has pointed to these proteins being amyloid promoters. However, the genetic data alone could not exclude the possibility that, for instance, apoE is an amyloid inhibitor with apoE4 being a less effective inhibitor than apoE3. Indeed, following our and other lab’s reports that apoE
The involvement of IL-1 in the AD pathogenic pathway
Soon after the discovery of ACT in the amyloid deposits, another important piece of biochemical evidence suggesting the presence of inflammation in AD was provided by Griffin et al. [23], [72]. They showed that the activated microglia in affected areas of the AD brain express large amounts of the inflammatory cytokine IL-1. This discovery was particularly interesting to us because IL-1 is the cytokine that upregulates ACT expression in hepatocytes as part of the body’s acute phase response to
Epidemiological studies
The finding that ACT and apoE are overexpressed in astrocytes in areas of Alzheimer brain showing pathology has also led to examinations of ACT levels in serum and cerebral spinal fluid (CSF) (for example: [37], [38]; for review, see [53]). The majority of studies find ACT to be significantly elevated in the serum and CSF of AD patients, thus confirming the presence of inflammation that can be detected before death.
In addition to the biochemical and pathological evidence that inflammation plays
Genetic support for the involvement of apoE, ACT, and IL-1 in Alzheimer’s disease
Since the finding that ACT and apoE, especially apoE4, are amyloid promoters in vitro, many other proteins have been tested and some have been found to affect Aβ polymerization (for review see [53]). However, thus far, ACT and apoE are the only potential pathological chaperones for which genetic studies also support their involvement in the Alzheimer pathogenic pathway. For example, as discussed above, one of the greatest genetic risk factors for developing Alzheimer’s disease is the
Alzheimer amyloid formation in vivo—proving the chaperone hypothesis with transgenic mice
The role of apoE in amyloid formation has recently been clarified by a series of in vivo experiments that confirm it to be an amyloid promoter [7], [26]. First, a set of mouse strains were developed that expressed transgenic human APP but which had their apoE gene either half (heterozygous) or completely (homozygous) knocked out. The animals showed a variable amount and speed of amyloid deposition that was dependent on the number of copies of the apoE gene: If there were no apoE genes, mature,
Behavioral studies
Finally, we have tested the various lines of transgenic mice in behavioral tasks of memory and cognition, including the radial arm water maze developed by Arendash and Diamond that is very sensitive to amyloid deposits [22], [46]. The preliminary results indicate that the apoE and ACT proteins are needed not only for amyloid formation but also for cognitive decline and memory loss in transgenic mouse models of AD (Nilsson, Potter and Arendash in preparation).
Summary
The transgenic animal experiments cap a long series of studies indicating that ACT and apoE and the inflammatory processes that produce these proteins contribute importantly and probably essentially to both amyloid formation and cognitive decline in Alzheimer’s disease. Together, the results suggest the basic outlines of a potential pathogenic pathway in Alzheimer’s disease that begins with small amounts of Aβ peptide oligomers or protofilaments, is amplified by an IL-1-driven inflammatory
Implications for therapeutic intervention
In addition to the potential therapeutic benefit of general anti-inflammatory drugs suggested by the epidemiological studies, the biochemical experiments identify potential foci of more specific therapeutic intervention. For example, it may be possible to develop molecules that inhibit the interaction between ACT and Aβ or between apoE and Aβ and prevent the accelerated formation of amyloid filaments. We have already begun to identify such molecules in the form of Aβ-related peptides [42]. The
Acknowledgements
The work of the lab has been supported by grants from the NIH, the Alzheimer’s Association, and private donors. H.P. occupies the Eric Pfeiffer Chair for Research on Alzheimer’s Disease at the Suncoast Gerontology Center at the University of South Florida. L.N.G.N. is supported by a fellowship from the John Douglas French Alzheimer’s Foundation.
References (84)
- et al.
Immunochemical identification of the serine protease inhibitor α1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease
Cell
(1988) - et al.
The protease inhibitor α1-antichymotrypsin is associated solely with amyloid deposits containing the b-protein and is localized in specific cells of both normal and diseased brain
Neurobiol Aging
(1990) - et al.
Expression of the Alzheimer amyloid-promoting factor antichymotrypsin is induced in human astrocytes by IL-1
Neuron
(1995) - et al.
Inflammatory mechanisms in Alzheimer’s disease
TIPS
(1994) - et al.
α-antichymotrypsin gene polymorphism and risk for Alzheimer’s disease in the Spanish population
Neurosci Lett
(1998) - et al.
Correlation between working memory deficits and Aβ deposits in transgenic APP+PS1 mice
Neurobiol Aging
(2001) - et al.
No genetic effect of α-1-antichymotrypsin in Alzheimer’s disease
Genomics
(1996) - et al.
Absence of association of α1-antichymotrypsin polymorphisms with Alzheimer’s diseasea report on autopsy-confirmed cases
Exp Neurol
(1998) - et al.
Visualization of A beta 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonalsevidence that an initially deposited species is Aβ 42(43)
Neuron
(1994) - et al.
Alzheimer’s peptide Aβ1-42 binds to two beta-sheets of α1-antichymotrypsin and transforms it from inhibitor to substrate
J Biol Chem
(1998)
Developmental expression of α1-antichymotrypsin in brain may be related to astrogliosis
Neurobiol Aging
Serum α1-antichymotrypsin as a marker for Alzheimer-type dementia
Neurobiol Aging
Promotion of the neurotoxicity of Alzheimer Aβ protein by the pathological chaperones ACT and apoE4inhibition by Aβ-related peptides and apoE2
Neurobiol Aging
Anti-inflammatory drugs and Alzheimer disease
Lancet
Astroglial expression of human α1-antichymotrypsin enhances Alzheimer-like pathology in amyloid protein precursor transgenic mice
Am J Pathol
Implication of α1-antichymotrypsin polymorphism in familial Alzheimer’s disease
Neurosci Lett
Effect of interleukin-6, dexamethazone, dbcAMP, and the A/T-signal peptide polymorphism on the expression of α-1 antichymotrypsin in astrocytes. Significance for Alzheimer’s disease
Neurochem Internatl
Apolipoprotein E polymorphism and Alzheimer’s disease
Lancet
The involvement of astrocytes and an acute phase response in the amyloid deposition of Alzheimer’s disease
Expression of immune system-associated antigens by cells of the human central nervous systemrelationship to the pathology of Alzheimer’s disease
Neurobiol Aging
Apolipoprotein Ea pathological chaperone in patients with cerebral and systemic amyloid
Neurosci Lett
Specific regional transcription of apolipoprotein E in human brain neurons
Am J Pathol
Alzheimer’s diseaserecent advances in understanding the brain amyloid deposits
Biotechnology
Über eine eigenartige Erkrankung der Hirnride
Allg Z Psychiatr Psych-Gerichtl
Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer’s disease? The Rotterdam Study
Neurology
Risk for Alzheimer’s disease correlates with transcriptional activity of the apoE gene
Hum Mol Genet
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Nat Genet
Interaction among hepatocyte-stimulating factors, interleukin-1, and glucocorticoids for regulation of acute phase plasma proteins in human hepatoma cells
J Immun
Inverse association of anti-inflammatory treatments and Alzheimer’s diseaseinitial results of a co-twin control study
Neurology
A polymorphism in the regulatory region of ApoE associated with risk for Alzheimer’s dementia
Nat Genet
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families
Science
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Nat Genet
NeuroReport
α1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation
Proc Natl Acad Sci USA
Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formationimplications for the pathogenesis and treatment of Alzheimer’s disease
Proc Natl Acad Sci USA
Effects of NSAIDs on IL-1β-induced IL-6 mRNA and protein synthesis in human astrocytoma cells
Neuroreport
a1-antichymotrypsin binding to Alzheimer Aβ peptides is sequence specific and induces fibril disaggregation in vitro
J Neurochem
Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein
Nature
Brain interleukin-1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer’s disease
Proc Natl Acad Sci USA
Apolipoproteins E receptors linking brain development and Alzheimer’s disease
Nature Reviews/Neurosci
Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease
Proc Natl Acad Sci USA
Nature Struct Biol
Cited by (70)
Blood-based biomarkers of cerebral small vessel disease
2024, Ageing Research ReviewsAstrogliosis and episodic memory in late life: higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer's disease
2021, Neurobiology of AgingCitation Excerpt :Preclinical animal studies highlight pivotal physiological roles for astrocytes in forming the tripartite synapse, regulating synaptic function, and modulating hippocampal-based memory consolidation (Adamsky et al., 2018; Ota et al., 2013). In the context of dysregulation, astrocytic (A1) activation has also been directly linked with hippocampal neuronal loss, memory deficits, and AD pathology in mouse models (Potter et al., 2001; Zhang et al., 2020). As such, a role for GFAP specifically in memory retention is intuitive and well-founded.
APOE-amyloid interaction: Therapeutic targets
2020, Neurobiology of DiseaseExosomal biomarkers in Down syndrome and Alzheimer's disease
2018, Free Radical Biology and MedicineCitation Excerpt :This is an expanding field that holds promise with regard to exosomal pathways and their role(s) in neurodegenerative pathways, as well as for the development of novel therapies for DS-AD, for AD, and for other neurodegenerative conditions. Since the 1980s, studies of post mortem brain specimens from AD patients have revealed significant elevations in neuroinflammatory markers [119,46,47,6,97]. Pro-inflammatory processes represent a normal innate immune response to pathogen invasion that is critical for initiating tissue repair and maintaining homeostasis.
Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor Protein Transgenic mice
2015, Journal of Biological Chemistry