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Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease.

Gentier RJ, Verheijen BM, Zamboni M, Stroeken MM, Hermes DJ, Küsters B, Steinbusch HW, Hopkins DA, Van Leeuwen FW - Front Neuroanat (2015)

Bottom Line: Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles.UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques.UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB(+1) distribution in the brains of transgenic mouse line 3413 overexpressing UBB(+1). We also mapped the expression of UBB(+1) in brain areas of AD patients selected based upon the distribution of UBB(+1) in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB(+1) positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB(+1) accumulates in their cellular hallmarks.

No MeSH data available.


Related in: MedlinePlus

UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human IC. (A) Representative photomicrograph of a 50 μm-thick coronal section from the brainstem of patient #6 (Braak 5). (B–E) Higher magnifications of the boxed region in (A) incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. The IC show selective vulnerability to Aβ accumulation, expressing a high number of both neuritic (star) and non-neuritic (arrow) plaques. Neuronal staining, represented by NFTs and UBB+1-immunoreactive substrates, is not present in this region. Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; CIC, central nucleus of IC; DCIC, dorsal cortex of IC; DR, dorsal raphe nucleus; ECIC, external cortex of IC; IC, inferior colliculus.
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Figure 7: UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human IC. (A) Representative photomicrograph of a 50 μm-thick coronal section from the brainstem of patient #6 (Braak 5). (B–E) Higher magnifications of the boxed region in (A) incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. The IC show selective vulnerability to Aβ accumulation, expressing a high number of both neuritic (star) and non-neuritic (arrow) plaques. Neuronal staining, represented by NFTs and UBB+1-immunoreactive substrates, is not present in this region. Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; CIC, central nucleus of IC; DCIC, dorsal cortex of IC; DR, dorsal raphe nucleus; ECIC, external cortex of IC; IC, inferior colliculus.

Mentions: In the IC, specifically the CIC was severely affected with plaques in 100% of AD cases, independent of Braak stage. By contrast, the DCIC and the ECIC subnuclei were relatively spared. The inferior colliculi showed selective vulnerability to Aβ accumulation, expressing a high number of both neuritic and non-neuritic plaques (Table 5, Figure 7). However, neuronal expression of (pre)-tangles and UBB+1-immunoreactive substrates was not present in these regions (Table 5, Figure 7).


Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease.

Gentier RJ, Verheijen BM, Zamboni M, Stroeken MM, Hermes DJ, Küsters B, Steinbusch HW, Hopkins DA, Van Leeuwen FW - Front Neuroanat (2015)

UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human IC. (A) Representative photomicrograph of a 50 μm-thick coronal section from the brainstem of patient #6 (Braak 5). (B–E) Higher magnifications of the boxed region in (A) incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. The IC show selective vulnerability to Aβ accumulation, expressing a high number of both neuritic (star) and non-neuritic (arrow) plaques. Neuronal staining, represented by NFTs and UBB+1-immunoreactive substrates, is not present in this region. Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; CIC, central nucleus of IC; DCIC, dorsal cortex of IC; DR, dorsal raphe nucleus; ECIC, external cortex of IC; IC, inferior colliculus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362318&req=5

Figure 7: UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human IC. (A) Representative photomicrograph of a 50 μm-thick coronal section from the brainstem of patient #6 (Braak 5). (B–E) Higher magnifications of the boxed region in (A) incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. The IC show selective vulnerability to Aβ accumulation, expressing a high number of both neuritic (star) and non-neuritic (arrow) plaques. Neuronal staining, represented by NFTs and UBB+1-immunoreactive substrates, is not present in this region. Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; CIC, central nucleus of IC; DCIC, dorsal cortex of IC; DR, dorsal raphe nucleus; ECIC, external cortex of IC; IC, inferior colliculus.
Mentions: In the IC, specifically the CIC was severely affected with plaques in 100% of AD cases, independent of Braak stage. By contrast, the DCIC and the ECIC subnuclei were relatively spared. The inferior colliculi showed selective vulnerability to Aβ accumulation, expressing a high number of both neuritic and non-neuritic plaques (Table 5, Figure 7). However, neuronal expression of (pre)-tangles and UBB+1-immunoreactive substrates was not present in these regions (Table 5, Figure 7).

Bottom Line: Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles.UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques.UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB(+1) distribution in the brains of transgenic mouse line 3413 overexpressing UBB(+1). We also mapped the expression of UBB(+1) in brain areas of AD patients selected based upon the distribution of UBB(+1) in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB(+1) positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB(+1) accumulates in their cellular hallmarks.

No MeSH data available.


Related in: MedlinePlus