Amyloid Precursor Protein mRNAs in Alzheimer's Disease

Harrison, Paul J.; Wighton-Benn, W H; Heffernan, Julia; Sanders, Maurice W.; Pearson, R.C.A.

doi:10.1006/neur.1996.0055

Cited by 12 publications

(7 citation statements)

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“…LRP has also been shown to interact directly with the extracellular domain of APP through its Kunitz-type serine protease inhibitor (KPI) domain and also indirectly with the cytoplasmic tail of APP through a common adaptor protein FE65 (Kinoshita et al, 2001; Knauer et al, 1996; Kounnas et al, 1995; Pietrzik et al, 2004; Trommsdorff et al, 1998). Interestingly, an increase in KPI containing isoforms of APP protein levels has been reported in AD (Harrison et al, 1996; Moir et al, 1998; Preece et al, 2004). Furthermore, it has been shown that LRP facilitates APP endocytic trafficking and amyloidogenic processing by bringing both APP and β-secretase into close proximity (Pietrzik et al, 2002; Ulery et al, 2000).…”

Section: Discussionmentioning

confidence: 92%

Association of ApoE and LRP mRNA levels with dementia and AD neuropathology

Akram

Schmeidler

Katsel

et al. 2012

Neurobiology of Aging

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Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk factor for late onset AD. ApoE is also a key ligand for LRP, a major neuronal LDL receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by qPCR and Western blotting. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indices of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared to those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in Aβ and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.

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Section: Discussionmentioning

confidence: 92%

Association of ApoE and LRP mRNA levels with dementia and AD neuropathology

Akram

Schmeidler

Katsel

et al. 2012

Neurobiology of Aging

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“…The details of the cases have been documented extensively (Lowe et al ., 1988 ;Harrison et al ., 1991 a;A. W. Procter et al ., submitted) and are summarized in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

“…APP mRNAs were detected in 15-gym sections of frontal cortex (Brodmann area 9/46) processed for in situ hybridization histochemistry (ISHH) using 35 S-labelled oligonucleotides as described (Harrison et al ., 1991 a). Incubation was carried out overnight at 27°C with 1 x 10 6 cpm of labelled probe in 100 wl of hybridization buffer.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we expressed the APP mRNA signal relative to that arising from hybridization to the poly(A) tails of polyadenylated [poly(A) + ] mRNA on other sections from each block ; this corrects at least partially for differences in overall mRNA content between individual brains and diagnostic groups (Harrison et al ., 1991(Harrison et al ., b, 1993 .…”

Section: Methodsmentioning

confidence: 99%

“…Although postmortem interval, which may affect APP mRNA (Burke et al, 1991), has been controlled for in most studies, these potentially confounding premonem influences have not . For example, terminal coma affects muscarinic ml receptor mRNA (Harrison et al ., 1991 a), whereas seizures and hypoxia affect other mRNAs (Burke et al, 1991). APP mRNA expression in the rat central nervous system is increased following hypoxia (Abe et al, 1991x) and injury (Scott et al ., 1991 ;Wallace et al, 1991 ;Solà et al, 1993x) and in cell culture by pyrexia (Abe et al, 1991 b).…”

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confidence: 99%

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The Effects of Alzheimer's Disease, Other Dementias, and Premortem Course on β‐Amyloid Precursor Protein Messenger RNA in Frontal Cortex

Harrison

Barton

Procter³

et al. 1994

Journal of Neurochemistry

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There are conflicting data regarding alterations in ß-Amyloid precursor protein (APP) mRNAs in Alzheimer's disease (AD) . This may be due partly to variables such as agonal state and choice of control group . We have used in situ hybridization histochemistry to study expression of APP mRNAs, with and without the domain encoding the Kunitz protease inhibitor, in a way that overcomes some of the limitations of the current data . Tissue from frontal cortex was collected at rapid autopsy from patients with AD or other cognitive impairments whose terminal phase was prospectively assessed . There were three main findings . Firstly, the amount of APP mRNAs correlated strongly with glutamate decarboxylase activity and was reduced in association with terminal pyrexia . These correlations suggest that agonal state affects APP mRNA and, therefore, that differences in premortem course may contribute to the varying changes in APP transcript abundance reported in AD . Secondly, a reduction of both forms of APP mRNA, normalized to polyadenylated mRNA, was found in AD compared with normal controls and with non-AD dementias. This supports findings that the APP-related pathology of AD is not due to overexpression of APP mRNA or an altered proportion of Kunitz protease inhibitor-containing isoforms . Thirdly, the amount of APP mRNA correlated inversely with that of heat-shock protein (hsx70) mRNA . This relationship was unexpected given current theories that APP expression occurs as part of a stress response, and suggests that other factors predominate in determining neocortical APP mRNA content in neurodegenerative disorders . Key Words : Agonal state-Alzheimer's disease-ß-Amyloid-Gene expression-Heat shock-In situ hybridization-mRNA .

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