Decreased pH in the aging brain and Alzheimer's disease

Decker, Yann; Németh, Eszter; Schomburg, Robert; Chemla, Axel; Fülöp, Lívia; Menger, Michael D.; Liu, Yang; Faßbender, Klaus

doi:10.1016/j.neurobiolaging.2020.12.007

Cited by 66 publications

(58 citation statements)

References 61 publications

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“…The chaperoning capacities of BRICHOS domain against amyloid neurotoxicity and fibril formation can apparently be modulated by a conserved Asp in response to pH changes. In the human brain, pH decreases with aging (56), and also pH is significantly lower in patients than in heathy controls in different human brain disorders (53,57). The observed phenomenon in this study suggests the possibility that microenvironmental changes may lead to human disease.…”

Section: Discussionsupporting

confidence: 48%

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Chen

Andrade-Talavera

Zhong

et al. 2021

Preprint

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Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but the respective mechanisms are not fully understood. The BRICHOS domain constitutes a disease-associated small heat shock protein-like chaperone family, with activities against both amyloid toxicity and amorphous protein aggregation. Here, we show that the activity of two BRICHOS domain families against Alzheimer’s disease associated amyloid-β neurotoxicity to mouse hippocampi in vitro depends on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The conserved Asp in its ionized state promotes structural flexibility of the BRICHOS domain and has a pKa value between pH 6.0–7.0, suggesting that chaperone effects against amyloid toxicity can be affected by physiological pH variations. Finally, the Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families and animal species, indicating independent evolution of molecular chaperone activities against amyloid fibril formation and non-fibrillar amorphous protein aggregation.

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Section: Discussionsupporting

confidence: 48%

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Chen

Andrade-Talavera

Zhong

et al. 2021

Preprint

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“…Our finding of an effect in AD, but not PD or HD, suggests that RNA degradation is specific to AD, rather than being a feature of neurodegenerative disease in general. Previous studies have reported a correlation between tissue pH and RIN ( Webster, 2006 ; Chevyreva et al, 2008 ), and that pH is decreased in AD brain tissue relative to neurologically normal controls ( Decker et al, 2021 ). It is possible therefore, that the effect of disease on RIN is mediated by pH.…”

Section: Discussionmentioning

confidence: 94%

RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer’s Disease

Highet

Parker

Faull

et al. 2021

Front. Mol. Neurosci.

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Gene expression studies of human post-mortem brain tissue are useful for understanding the pathogenesis of neurodegenerative disease. These studies rely on the assumption that RNA quality is consistent between disease and neurologically normal cases; however, previous studies have suggested that RNA quality may be affected by neurodegenerative disease. Here, we compared RNA quality in human post-mortem brain tissue between neurologically normal cases (n = 14) and neurodegenerative disease cases (Alzheimer’s disease n = 10; Parkinson’s disease n = 11; and Huntington’s disease n = 9) in regions affected by pathology and regions that are relatively devoid of pathology. We identified a statistically significant decrease in RNA integrity number (RIN) in Alzheimer’s disease tissue relative to neurologically normal tissue (mixed effects model, p = 0.04). There were no statistically significant differences between neurologically normal cases and Parkinson’s disease or Huntington’s disease cases. Next, we investigated whether total RNA quality affected mRNA quantification, by correlating RIN with qPCR threshold cycle (CT). CT values for all six genes investigated were strongly correlated with RIN (p < 0.05, Pearson correlation); this effect was only partially mitigated by normalization to RPL30. Our results indicate that RNA quality is decreased in Alzheimer’s disease tissue. We recommend that RIN should be considered when this tissue is used in gene expression analyses.

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“…106 Therefore, it is important to delineate the conditions which flip the switch of physiological-to-pathological Tau aggregation in the brain. These may include (1) regional vulnerability of the brain circuits to Tau aggregation, (2) neuronal and non-neuronal cell type vulnerability, such as increased susceptibility of the excitatory presynaptic neurons, 107 (3) emergence of particularly toxic Tau protein subpopulations due to PTMs or associations with cofactor molecules or other amyloidogenic proteins, such as amyloid-b, 108 (4) local changes in the brain and cerebrospinal fluid (CSF) acidification levels, 109,110 as well as (5) subcellular mislocalization of Tau protein from axonal to somatodendritic compartments 111 that may contribute to Tau displacement from microtubules in cells 112 and subsequent aggregation. It is yet not fully understood which mechanisms contribute substantially to the inception and progression of human Tauopathies.…”

Section: Tau Contribution To Neurodegenerative Disordersmentioning

confidence: 99%

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Limorenko

Lashuel

2022

Chem. Soc. Rev.

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Decreased pH in the aging brain and Alzheimer's disease

Cited by 66 publications

References 61 publications

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

RNA Quality in Post-mortem Human Brain Tissue Is Affected by Alzheimer’s Disease

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

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