Immunohistochemical localization of beta‐amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy

McGeer, Patrick L.; Akiyama, Haruhiko; Kawamata, Toshio; Yamada, Tatsuo; Walker, Douglas G.; Ishii, Tsuyoshi

doi:10.1002/jnr.490310305

Cited by 88 publications

(34 citation statements)

References 41 publications

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“…81,82 Microglia might instead be primarily recruited to clear the fragmented and/or apoptotic neurons and neurites within the senile plaques, 83 as occurs during neurodevelopment. 84 As proposed previously, 33 microglial involvement in internalization of Aβ aggregates could, therefore, be interpreted as part of the process of clearing degenerating neurites that contain misfolded and damaged proteins.…”

Section: Aged and Primed Microgliamentioning

confidence: 83%

“…17 Finally, these APP accumulations might represent a seed for other aggregation-prone peptides ( Figure 1, step 5), as demonstrated in immune-challenged transgenic AD mice. 17 On the basis of recent observations in the brains of patients with AD, 28 we propose that axonal leakage and release of intracellular contents-especially from dense auto phagolysosomal vesicles 30 32 and diverse non-Aβ fragments of APP 33,34 in senile plaques. In addition, electron micro scopy of human senile plaques revealed, in accordance with this proposal, an abundance of mitochondria and other organelles, as well as degenerated neurites, in the plaque core.…”

Section: Inflammation Hypothesis Of Admentioning

confidence: 96%

“…In addition, electron micro scopy of human senile plaques revealed, in accordance with this proposal, an abundance of mitochondria and other organelles, as well as degenerated neurites, in the plaque core. 33,35 Finally, the pro inflammatory environment and concomitant loss of axons might lead to formation of NFTs and neuronal cell death ( Figure 1, step 6). This suggestion is in agreement with the observation that formation of NFT-like structures in AD transgenic mice-importantly, in the absence of mutant human tau-was accompanied by aggravated Aβ deposition, prominent neuroinflammation and considerable shrinkage of cortical areas.…”

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

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Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Section: Aged and Primed Microgliamentioning

confidence: 83%

Section: Inflammation Hypothesis Of Admentioning

confidence: 96%

Section: Inflammation Hypothesis Of Admentioning

confidence: 99%

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Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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“…Instead, antibodies to diverse sequences in APP immunostain punctuate granules within the cytoplasm of normal appearing neurons in both control and AD cases. These are concentrated in the perinuclear region and extend into neuronal processes (12)(13)(14)(15)(16). The nature of these granules is unknown, but they indicate that APP accumulates intracellularly.…”

Section: Discussionmentioning

confidence: 99%

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Jian-ping

Arai

Miklóssy

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

223

202

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To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-␤ protein (A␤). This complex enhances tau phosphorylation by GSK3␤, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A␤ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A␤ peptides in the mid to C-terminal regions of A␤. This binding is also significantly decreased by GSK3␤ phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A␤ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A␤ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and A␤ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A␤ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A␤ nucleation. Blocking the sites where A␤ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.immunochemistry ͉ neurofibrillary tangles ͉ senile plaques ͉ surface plasmon resonance S o far, no reasonable interpretation has been advanced to explain the simultaneous appearance of senile plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Senile plaques develop extracellularly with the main component being aggregated amyloid-␤ protein (A␤), whereas NFTs develop intracellularly with the main component being aggregated forms of phosphorylated tau. The two aggregation processes appear to occur independently, because NFTs develop in neuronal cell bodies and senile plaques develop around their nerve endings. This observation has led to two schools of thought regarding AD causation. The tau hypothesis holds that the disease is driven by tangles resulting from an excess of tau phosphorylation or a deficiency of its dephosphorylation (1). The hypothesis does not explain plaques. The amyloid hypothesis holds that the disease is driven by excess production of A␤ (2, 3). This hypothesis does not explain NFTs. Nevertheless, the amyloid cascade hypothesis is dominant because mutations in amyloid precursor protein (APP), which enhance A␤ production, cause autosomal dominant AD but not other types of dementia (2). On the other hand, mutations in tau that promote tau aggregation produce autosomal dominant frontotemporal dementia but not AD (4, 5). As a result, the presumption is that excess A␤ is a major cause and an upstream event of AD tangle formation, but exactly how an A␤ excess ...

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“…Such a consolidated microglia-amyloid space may give rise to leakage of cytotoxic and inflammatory microglial proteins into the surrounding neuropil. 10 However, an open microglia membrane clearly suggests amyloidassociated microglia cell death. In APP23 mice we have not observed convincing evidence for microglia cell death around amyloid plaques, although recent observations in AD brain suggest that amyloid-associated microglial cell death may indeed occur.…”

Section: Discussionmentioning

confidence: 99%

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Stalder¹,

Phinney²,

Probst³

et al. 1999

The American Journal of Pathology

305

201

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Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD , the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between ␤-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-␤ precursor protein (␤PP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14-to 18-month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1-and phosphotyrosinepositive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice , early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally , bundles of amyloid fibrils , sometimes surrounded by an incomplete membrane , were observed within the microglial cytoplasm. However , microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal , contributory , or consequential to cerebral amyloidosis , our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived ␤PP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived ␤PP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice. (Am J Pathol 1999, 154:1673-1684)Substantial evidence supports the view that processing of the amyloid-␤ precursor protein (␤PP) and accumulation of the amyloid-␤ peptide (A␤) in the brain of Alzheimer's disease (AD) patients is crucial to the pathophysiology of the disease. 1,2 Senile amyloid plaques in AD brains are surrounded and infiltrated by activated microglia, which acquire an amoeboid morphology and express various proteins involved in the central nervous system inflammation. [3][4][5] The tight association of amyloid fibrils and microglia has suggested that microglia are somehow involved in either the formation or the phagocytosis of amyloid fibrils. 3,6 -10 Activation of microglia is thought to induce an inflammatory response in the central nervous system and to be a mediator of the amyloid-associated neurodegeneration in AD brain. 11,12 The involvement of inflammation in the progress of AD is underlined by clinical studies showing...

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Immunohistochemical localization of beta‐amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy

Cited by 88 publications

References 41 publications

Deciphering the mechanism underlying late-onset Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

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