Hearing loss linked to accelerated Alzheimer's progression via GDF1 pathway

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In a recent study published in the journal Nature Aging, researchers investigated how hearing loss intensifies cognitive decline through the embryonic growth/differentiation factor 1 (GDF1) signaling pathway, offering potential therapeutic insights for Alzheimer's disease (AD).

Study: GDF1 ameliorates cognitive impairment induced by hearing loss. Image Credit: Ground Picture / ShutterstockStudy: GDF1 ameliorates cognitive impairment induced by hearing loss. Image Credit: Ground Picture / Shutterstock

Background 

Epidemiological evidence links hearing loss to an increased risk of dementia, particularly AD, which is marked by amyloid β (Aβ) plaques and tau tangles. The exact mechanisms are unclear, but hearing loss may accelerate AD pathology. Studies suggest that mitigating hearing loss could reduce AD risk and cognitive decline. Further research is needed to fully elucidate the molecular mechanisms linking GDF1 to hearing loss and AD, paving the way for potential therapeutic interventions.

About the study 

In the present study, the researchers utilized both wild-type (WT) C57BL/6J mice and amyloid precursor protein (APP)/presenilin 1 (PS1) mice, the latter genetically modified to express mutations associated with AD, displaying Aβ deposits in the brain by around 6 to 7 months of age. These mice were bred, and their offspring were identified through polymerase chain reaction (PCR) analysis of tail deoxyribonucleic acid (DNA), focusing on males aged 3 to 4 months. Maintained under specific pathogen-free conditions and a controlled light-dark cycle, the mice were subjected to approved experimental protocols.

Surgical and pharmacological methods were applied to induce hearing loss. Through a thorough procedure involving anesthesia, incision, and manipulation of the middle ear, cochlear ablation (CA) was performed to simulate hearing loss, while a sham surgery served as a control. Additionally, hearing loss was pharmacologically induced by administering kanamycin, a method validated in previous studies that closely monitored the mice's health and adjusted dosages accordingly.

Auditory brainstem response (ABR) recording, a key technique, assessed the hearing capabilities of these mice, utilizing a range of sound frequencies and intensities. This helped confirm the efficacy of the hearing loss models. Furthermore, gene therapy techniques were employed to modulate the expression of GDF1 within the hippocampus, either increasing or decreasing its levels through the use of adeno-associated viruses (AAV), aiming to study its impact on cognitive functions in the context of Alzheimer's disease pathology.

The researchers precisely detailed the reagents and antibodies used, ensuring the specificity and reliability of their immunoblotting and immunostaining protocols. Techniques such as ribonucleic acid (RNA) sequencing, cell culture, and various biochemical assays complemented the study, offering insights into the molecular pathways influenced by GDF1 expression and its potential protective effects against AD progression. Electrophysiological recordings and behavioral tests further elucidated the functional implications of GDF1 modulation, assessing synaptic function and memory capabilities.

Study results 

The study explored the impact of hearing loss on AD, such as pathology and cognitive functions, by conducting bilateral CA on both WT and APP/PS1 transgenic mice, which are genetically predisposed to develop AD. ABR confirmed hearing loss in CA mice, with increased Aβ deposition in the hippocampus and auditory cortex observed as early as 3 months post-surgery in APP/PS1 mice. Interestingly, the levels of APP and its proteolytic C-terminal fragments (CTFs) were elevated in the hippocampus of deaf mice, suggesting an acceleration of AD pathology due to hearing loss.

To assess cognitive functions, Morris water maze and Y-maze tests were administered, revealing impaired spatial memory and working memory in both WT and APP/PS1 mice with hearing loss. Further investigations into synaptic function showed reduced synaptic density and compromised synaptic plasticity in the hippocampus of deaf mice, highlighting synaptic dysfunction as a key contributor to the observed cognitive impairments.

Another aspect of the study involved a kanamycin-induced hearing loss model to confirm the findings. Similar to CA, kanamycin treatment resulted in significant hearing loss, increased Aβ deposition, and cognitive deficits, reinforcing the notion that hearing loss exacerbates AD-like pathology.

Focusing on the underlying mechanisms, messenger RNA (mRNA) sequencing identified the downregulation of GDF1 in the hippocampus of mice with hearing loss. GDF1, a member of the transforming growth factor-β superfamily, was shown to be crucial in reducing the adverse effects of hearing loss on cognition and AD pathology. Overexpression of GDF1 in the hippocampus of deaf mice via AAVs ameliorated spatial learning and memory impairments, reduced Aβ plaque load, and reversed synaptic protein level reductions, indicating its protective role against hearing loss-induced cognitive decline and AD-like changes.

The study further clarified that GDF1 activation leads to the inhibition of asparagine endopeptidase (AEP), a key enzyme in APP processing and Aβ production, through the protein kinase B (Akt) signaling pathway. Conversely, the knockdown of GDF1 mimicked the detrimental effects of hearing loss, suggesting that GDF1 downregulation is a pivotal factor in hearing loss-induced AD pathology. Lastly, the investigation into transcriptional regulation uncovered that CCAAT-enhancer binding protein-β (C/EBPβ) suppresses GDF1 expression, indicating a potential target for therapeutic intervention. 

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    

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