Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

Kumar, Prateek; Goettemoeller, Annie M.; Espinosa-Garcia, Claudia; Tobin, Brendan R.; Tfaily, Ali; Nelson, Ruth S.; Natu, Aditya; Dammer, Eric B.; Santiago, Juliet V.; Malepati, Sneha; Cheng, Lihong; Xiao, Hailian; Duong, Duc D.; Seyfried, Nicholas T.; Wood, Levi B.; Rowan, Matthew J. M.; Rangaraju, Srikant

doi:10.1038/s41467-024-47028-7

Cited by 6 publications

(8 citation statements)

References 164 publications

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“…1i). This was achieved through systemic AAV injections to achieve whole-cortex expression of a PV-specific, Cre-expressing enhancer-AAV in Flex.TurboID mice 21 followed by region-specific microdissection (Fig. 1i; Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although a comparison of PV-CIBOP regional proteomes with bulk human brain proteomes gives further insight into potential cell-type-specific alterations in phases of AD, it is still limited by the inability to verify PV interneuron-specificity of observed changes in human brain. As we only recently established the first, to our knowledge, PV interneuron-specific proteome 21 , we look forward to the advancement of techniques to come in order to complete such a level of analysis in human tissue. Future studies at the single-cell level in humans with early-stage AD will be necessary to confirm this assertion.…”

Section: Discussionmentioning

confidence: 99%

“…PV-CIBOP studies were performed by single retro-orbital injections of AAV(AAV(PHP.eB).E2.Cre.2A.GFP) as described above to Rosa26TurboID/wt mice and WT littermate animals at 7 weeks of age, as previously described 21 . Control groups in PV-CIBOP studies also received AAV E2.Cre injections for fair comparisons.…”

Section: Methodsmentioning

confidence: 99%

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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Goettemoeller,

Banks,

Kumar

et al. 2023

Preprint

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Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability1. In mouse models, early hyperexcitability has been shown in the entorhinal cortex, the first cortical region impacted by Alzheimer’s Disease2-4. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type-specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific amyloid precursor protein (hAPP) in a model of sporadic Alzheimer’s. Unexpectedly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, rather than the suspected layer II excitatory neurons. This vulnerability of entorhinal PV interneurons is specific to hAPP, as it could not be recapitulated with increased murine APP expression. Furthermore, the Somatosensory Cortex showed no such vulnerability to adult-onset hAPP expression, likely resulting from PV-interneuron variability between the two regions based on physiological and proteomic evaluations. Interestingly, entorhinal hAPP-induced hyperexcitability was quelled by co-expression of human Tau at the expense of increased pathological tau species. This study suggests early disease interventions targeting non-excitatory cell types may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Goettemoeller,

Banks,

Kumar

et al. 2023

Preprint

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“…PV+ inhibitory interneuron dysfunction has now been identified as one of the earliest pathophysiological perturbations in AD [129]. Altered E/I balance and impaired GABAergic signaling are known risk factors for AD [130,131].…”

Section: Pv+ Interneuron Dysfunction In Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…Various studies suggest inhibitory interneurons, especially PV+ interneurons, are susceptible to mitochondrial impairment. Proteomic analysis using cell-type-specific in vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state proteomes of PV interneurons has revealed strong correlations between PV+ interneuronspecific proteome signatures and progressive neuropathology in humans and mouse models of Aβ pathology [129]. Analysis revealed unique signatures of increased mitochondrial and metabolic proteins in response to early Aβ pathology.…”

Section: Targeting Pv+ Interneurons In Future Treatment Strategies Fo...mentioning

confidence: 99%

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

Leitch

2024

IJMS

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Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their dysfunction can lead to hyperexcitability and increased susceptibility to seizures. PV+ interneurons are also key players in generating gamma oscillations, which are synchronized neural oscillations associated with various cognitive functions. PV+ interneuron are particularly vulnerable to aging and their degeneration has been associated with cognitive decline and memory impairment in dementia and Alzheimer’s disease (AD). Overall, dysfunction of PV+ interneurons disrupts the normal excitatory/inhibitory balance within specific neurocircuits in the brain and thus has been linked to a wide range of neurodevelopmental and neuropsychiatric disorders. This review focuses on the role of dysfunctional PV+ inhibitory interneurons in the generation of epileptic seizures and cognitive impairment and their potential as targets in the design of future therapeutic strategies to treat these disorders. Recent research using cutting-edge optogenetic and chemogenetic technologies has demonstrated that they can be selectively manipulated to control seizures and restore the balance of neural activity in the brains of animal models. This suggests that PV+ interneurons could be important targets in developing future treatments for patients with epilepsy and comorbid disorders, such as AD, where seizures and cognitive decline are directly linked to specific PV+ interneuron deficits.

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H-Ras induces exuberant de novo dendritic protrusion growth in mature neurons regardless of cell type

Krüssel,

Deb,

Son

et al. 2024

iScience

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Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

Cited by 6 publications

References 164 publications

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

H-Ras induces exuberant de novo dendritic protrusion growth in mature neurons regardless of cell type

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