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Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimer's Disease Brain.

ABSTRACT: Synaptic dysfunction and loss occur in Alzheimer's disease (AD) brains, which results in cognitive deficits and brain neurodegeneration. Neuropeptides comprise the major group of synaptic neurotransmitters in the nervous system. This study evaluated neuropeptide signatures that are hypothesized to differ in human AD brain compared to age-matched controls, achieved by global neuropeptidomics analysis of human brain cortex synaptosomes. Neuropeptidomics demonstrated distinct profiles of neuropeptides in AD compared to controls consisting of neuropeptides derived from chromogranin A (CHGA) and granins, VGF (nerve growth factor inducible), cholecystokinin, and others. The differential neuropeptide signatures indicated differences in proteolytic processing of their proneuropeptides. Analysis of cleavage sites showed that dibasic residues at the N-termini and C-termini of neuropeptides were the main sites for proneuropeptide processing, and data also showed that the AD group displayed differences in preferred residues adjacent to the cleavage sites. Notably, tau peptide signatures differed in the AD compared to age-matched control human brain cortex synaptosomes. Unique tau peptides were derived from the tau protein through proteolysis using similar and differential cleavage sites in the AD brain cortex compared to the control. Protease profiles differed in the AD compared to control, indicated by proteomics data. Overall, these results demonstrate that dysregulation of neuropeptides and tau peptides occurs in AD brain cortex synaptosomes compared to age-matched controls, involving differential cleavage site properties for proteolytic processing of precursor proteins. These dynamic changes in neuropeptides and tau peptide signatures may be associated with the severe cognitive deficits of AD.

SUBMITTER: Podvin S

PROVIDER: S-EPMC9264367 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

Project description:Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.

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Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimer's Disease Brain.

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