Longitudinal, Quantitative Assessment of Amyloid, Neuroinflammation, and Anti-Amyloid Treatment in a Living Mouse Model of Alzheimer's Disease Enabled by Positron Emission Tomography

Laboratory for Proteolytic Neuroscience, RIKEN, Вако, Saitama, Japan
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2007; 27(41):10957-68. DOI: 10.1523/JNEUROSCI.0673-07.2007
Source: PubMed


We provide the first evidence for the capability of a high-resolution positron emission tomographic (PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[11C]methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (Abeta). Moreover, PET scans with [18F]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [11C]PIB. It is also noteworthy that the localization and abundance of [11C]PIB autoradiographic signals were closely associated with those of N-terminally truncated and modified Abeta, AbetaN3-pyroglutamate, in Alzheimer's disease (AD) and Tg mouse brains, implying that the detectability of amyloid by [11C]PIB positron emission tomography is dependent on the accumulation of specific Abeta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.

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Available from: Bin Ji, Sep 15, 2015
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    • "Importantly, some markers of glial activation are elevated even before the development of amyloid deposition, implying that neuroinflammation precedes typical AD neuropathological changes and has some causative effect in AD pathogenesis (Sheng et al., 2000). Recent high-resolution positron emission tomographic (PET) imaging has enabled longitudinal observation of amyloid accumulation and associated microglial activation in the Alzheimer amyloid precursor protein (APP) transgenic mouse, and demonstrated a dynamic change in microglial activity in response to anti-amyloid therapy (Maeda et al., 2007; Ji et al., 2008). "
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    ABSTRACT: The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD) is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plaques and neurofibrillary tangles (NFT), accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non-cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood-brain barrier (BBB) dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive/non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions.
    Frontiers in Aging Neuroscience 07/2014; 6:171. DOI:10.3389/fnagi.2014.00171 · 4.00 Impact Factor
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    • "Radiosynthesis and Small-Animal PET Imaging N- 11 C-methyl-2-(4 0 -methylaminophenyl)26-hydroxy- benzothiazole ( 11 C-PIB), which can react with amyloid fibrils and has a slow clearance from amyloid-rich regions compared with that from normal regions, resulting in a high-level retention of radioactivity in amyloid-rich regions in brain, is used as a potential PET imaging probe for identifying AD amyloid pathology in the human antecedent to clinical onset of AD (Klunk et al., 2004) and in laboratory AD model animals (Maeda et al., 2007). Protocols for radiosynthesis of 11 C-PIB and performance of mouse brain PET imaging were described in our previous article (Maeda et al., 2007). The radiochemical purity and specific radioactivity of 11 C-PIB at the end of synthesis exceeded 95% and 250 GBq/lmol, respectively. "
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    ABSTRACT: The cause and risk factors of Alzheimer's disease (AD) are largely unknown. Studies on possible radiation-induced AD-like pathogenesis and behavioral consequences are important because humans are exposed to ionizing radiation (IR) from various sources. It was reported that total-body irradiations (TBI) at 10 cGy of low linear energy transfer (LET) X-rays to mice triggered acute transcriptional alterations in genes associated with cognitive dysfunctions. However, it was unknown whether low doses of IR could induce AD-like changes late after exposure. We reported previously that 10 cGy X-rays induced early transcriptional response of several AD-related genes in hippocampi without late AD-like pathogenesis and memory impairment in mice. Here, further studies on two low doses (5 or 10 cGy) of high LET carbon-ion irradiations are reported. On expression of 84 AD-related genes in hippocampi, at 4 hr after TBI, 5 cGy induced a significant upregulation of three genes (Abca1, Casp3, and Chat) and 10 cGy led to a marked upregulation of one gene (Chat) and a downregulation of three genes (Apoe, Ctsd, and Il1α), and, at 1 year after TBI, one gene (Il1α) was significantly downregulated in 10 cGy-irradiated animals. Changes in spatial learning ability and memory and induction of AD-like pathogenesis were not detected by in vivo brain imaging for amyloid-β peptide accumulation and by immunohistochemical staining of amyloid precursor protein, amyloid-β protein, tau, and phosphorylated tau protein. These findings indicate that low doses of carbon-ion irradiations did not cause behavioral impairment or AD-like pathological change in mice. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 07/2014; 92(7). DOI:10.1002/jnr.23363 · 2.59 Impact Factor
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    • "This suggests that in the parenchyma, pyroglutamate Aβ-formation might represent a later step in plaque maturation which might depend on remodeling of existing extracellular deposits. The presence of pyroglutamate Aβ deposits in transgenic mouse models has been confirmed in a variety of studies demonstrating that pyroglutamate Aβ-immunoreactivity is mainly confined to the amyloid core [23, 33, 40, 55]. In order to verify the in vivo toxicity of pyroglutamate Aβ, mouse models expressing solely the respective peptide but not the entire human APP molecule have been developed. "
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    ABSTRACT: Although N-truncated Aβ variants are known to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease, their potential as targets for pharmacological intervention has only recently been investigated. In the last few years, the Alzheimer field has experienced a paradigm shift with the ever increasing understanding that targeting amyloid plaques has not led to a successful immunotherapy. On the other hand, there can be no doubt that the amyloid cascade hypothesis is central to the etiology of Alzheimer's disease, raising the question as to why it is apparently failing to translate into the clinic. In this review, we aim to refocus the amyloid hypothesis integrating N-truncated Aβ peptides based on mounting evidence that they may represent better targets than full-length Aβ. In addition to Aβ peptides starting with an Asp at position 1, a variety of different N-truncated Aβ peptides have been identified starting with amino residue Ala-2, pyroglutamylated Glu-3, Phe-4, Arg-5, His-6, Asp-7, Ser-8, Gly-9, Tyr-10 and pyroglutamylated Glu-11. Certain forms of N-truncated species are better correlates for early pathological changes found pre-symptomatically more often than others. There is also evidence that, together with full-length Aβ, they might be physiologically detectable and are naturally secreted by neurons. Others are known to form soluble aggregates, which have neurotoxic properties in transgenic mouse models. It has been clearly demonstrated by several groups that some N-truncated Aβs dominate full-length Aβ in the brains of Alzheimer's patients. We try to address which of the N-truncated variants may be promising therapeutic targets and which enzymes might be involved in the generation of these peptides.
    Acta Neuropathologica 05/2014; 127(6). DOI:10.1007/s00401-014-1287-x · 10.76 Impact Factor
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