Cardiac remodeling, amyloidosis, neurotrophic signaling and innervation impairment in the Tg2576 model of Alzheimer’s disease
Andrea Elia, Rebecca M Parodi‐Rullan, Rafael Vazquez‐Torres, Ashley M Carey, Silvia Fossati- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
In Alzheimer’s disease (AD), the characteristic cerebral amyloid β (Aβ) accumulation and tau pathology, are accompanied by a gradual loss of the two main neuromodulators, NGF and BDNF. This AD‐mediated derangement of the brain’s neuro‐signaling pathways may extend to the periphery and, along with potential peripheral amyloid deposition, induce peripheral nervous system impairment, thus affecting other organs, including the heart. However, whether and how AD pathology affects cardiac physiology, neurotrophins, innervation, and heart amyloidosis is still undefined.
Method
Here, we describe for the first‐time that cardiac remodeling and neuro‐signaling dysregulation are present in the hearts of Tg2576 mice, a widely used model of AD and cerebral amyloidosis.
Results
Echocardiographic analysis showed significant deterioration of left ventricle function, as demonstrated by a decline of both ejection fraction and fraction shortening in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. The transgenic mice hearts presented an increase in interstitial fibrosis, with an accumulation of amyloid aggregates, including Aβ, associated with severe cardiac nervous system dysfunction. Tg2576 mice exhibited a depletion in cardiac nerve fiber density, both adrenergic (stained with tyrosine hydroxylase‐ TH) and regenerating nerve terminals (labeled with GAP‐43) compared to the WT mice. This myocardial denervation was accompanied by a decline in NGF and BDNF protein expression as well as GAP‐43 expression in both the brain and heart of Tg2576 mice. Likewise, both human neuroblastoma cells (SH‐SY5Y) and human cardiomyocytes (AC16) challenged with human Aβ‐40 or Aβ‐42 oligomers showed significant downregulation of both BDNF and GAP‐43 activity.
Conclusion
Overall, this study highlights the deleterious impact of cerebral amyloidosis on the cardiac nervous system and heart physiology, providing potential therapeutic targets, such as neurotrophic factors, to prevent or limit the AD‐mediated degenerative mechanisms on the cardiovascular system.