
In a recent study published within 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 / 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 precise mechanisms are unclear, but hearing loss may speed up AD pathology. Studies suggest that mitigating hearing loss could reduce AD risk and cognitive decline. Further research is required to completely elucidate the molecular mechanisms linking GDF1 to hearing loss and AD, paving the best way for potential therapeutic interventions.
In regards to the study
In the current study, the researchers utilized each wild-type (WT) C57BL/6J mice and amyloid precursor protein (APP)/presenilin 1 (PS1) mice, the latter genetically modified to precise mutations related to AD, displaying Aβ deposits within the brain by around 6 to 7 months of age. These mice were bred, and their offspring were identified through polymerase chain response (PCR) evaluation of tail deoxyribonucleic acid (DNA), specializing in 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 an intensive procedure involving anesthesia, incision, and manipulation of the center ear, cochlear ablation (CA) was performed to simulate hearing loss, while a sham surgery served as a control. Moreover, hearing loss was pharmacologically induced by administering kanamycin, a way 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 those mice, utilizing a spread of sound frequencies and intensities. This helped confirm the efficacy of the hearing loss models. Moreover, gene therapy techniques were employed to modulate the expression of GDF1 inside the hippocampus, either increasing or decreasing its levels through using adeno-associated viruses (AAV), aiming to review its impact on cognitive functions within 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 reminiscent of 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, reminiscent of pathology and cognitive functions, by conducting bilateral CA on each WT and APP/PS1 transgenic mice, that are genetically predisposed to develop AD. ABR confirmed hearing loss in CA mice, with increased Aβ deposition within the hippocampus and auditory cortex observed as early as 3 months post-surgery in APP/PS1 mice. Interestingly, the degrees of APP and its proteolytic C-terminal fragments (CTFs) were elevated within the hippocampus of deaf mice, suggesting an acceleration of AD pathology because of hearing loss.
To evaluate cognitive functions, Morris water maze and Y-maze tests were administered, revealing impaired spatial memory and dealing memory in each WT and APP/PS1 mice with hearing loss. Further investigations into synaptic function showed reduced synaptic density and compromised synaptic plasticity within the hippocampus of deaf mice, highlighting synaptic dysfunction as a key contributor to the observed cognitive impairments.
One other aspect of the study involved a kanamycin-induced hearing loss model to substantiate the findings. Just like CA, kanamycin treatment resulted in significant hearing loss, increased Aβ deposition, and cognitive deficits, reinforcing the notion that hearing loss exacerbates AD-like pathology.
Specializing in the underlying mechanisms, messenger RNA (mRNA) sequencing identified the downregulation of GDF1 within the hippocampus of mice with hearing loss. GDF1, a member of the reworking growth factor-β superfamily, was shown to be crucial in reducing the opposed effects of hearing loss on cognition and AD pathology. Overexpression of GDF1 within 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 results in 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 think about 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 possible goal for therapeutic intervention.