The unique neuropathological vulnerability of the human brain to aging

Ferrer, L.

doi:10.1016/j.arr.2023.101916

Cited by 8 publications

(1 citation statement)

References 578 publications

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“…The primary specific limitation of the present approach is the small number of cases ( n = 4 for every group). This is due to the rarity to find late-elderly individuals with no ADNC and without any other neuropathological lesion [ 51 ]. Due to their size, molecular properties, and methodological restraints, the limited capacity to detect numbers of proteins is a general curtailment of (phospho)proteomics studies, as well.…”

Section: Discussionmentioning

confidence: 99%

Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes

Andrés-Benito,

Íñigo-Marco,

Brullas

et al. 2023

Aging

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Aims: (Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and without AD-neuropathological changes and lacking any other neurodegenerative alteration will increase understanding about the physiological state of human brain aging without associate neurological deficits and neuropathological lesions. Methods: (Phospho)proteomics using conventional label-free- and SWATH-MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs, senile plaques (SPs) and age-related co-morbidities classified by age (years) in four groups; group 1 (young, 30–44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64–70); and group 4 (late-elderly, 75–85). Results: Protein levels and deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found in FC with age. The modified expression occurs in cytoskeleton proteins, membranes, synapses, vesicles, myelin, membrane transport and ion channels, DNA and RNA metabolism, ubiquitin-proteasome-system (UPS), kinases and phosphatases, fatty acid metabolism, and mitochondria. Dysregulated phosphoproteins are associated with the cytoskeleton, including microfilaments, actin-binding proteins, intermediate filaments of neurons and glial cells, and microtubules; membrane proteins, synapses, and dense core vesicles; kinases and phosphatases; proteins linked to DNA and RNA; members of the UPS; GTPase regulation; inflammation; and lipid metabolism. Noteworthy, protein levels of large clusters of hierarchically-related protein expression levels are stable until 70. However, protein levels of components of cell membranes, vesicles and synapses, RNA modulation, and cellular structures (including tau and tubulin filaments) are markedly altered from the age of 75. Similarly, marked modifications occur in the larger phosphoprotein clusters involving cytoskeleton and neuronal structures, membrane stabilization, and kinase regulation in the late elderly. Conclusions: Present findings may increase understanding of human brain proteostasis modifications in the elderly in the subpopulation of individuals not having AD neuropathological change and any other neurodegenerative change in any telencephalon region.

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Section: Discussionmentioning

confidence: 99%

Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes

Andrés-Benito,

Íñigo-Marco,

Brullas

et al. 2023

Aging

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Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Langerscheidt,

Wied,

Al Kabbani

et al. 2024

J Neurol

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Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

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In Situ Reprogramming of Neurons and Glia – A Risk in Altering Memory and Personality?

Tang

2023

AJOB Neuroscience

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The unique neuropathological vulnerability of the human brain to aging

Cited by 8 publications

References 578 publications

Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes

Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

In Situ Reprogramming of Neurons and Glia – A Risk in Altering Memory and Personality?

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