Axonal and myelinic pathology in 5xFAD Alzheimer’s mouse spinal cord

Abstract

As an extension of the brain, the spinal cord has unique properties which could allow us to gain a better understanding of CNS pathology. The brain and cord share the same cellular components, yet the latter is simpler in cytoarchitecture and connectivity. In Alzheimer’s research, virtually all focus is on brain pathology, however it has been shown that transgenic Alzheimer’s mouse models accumulate beta amyloid plaques in spinal cord, suggesting that the cord possesses the same molecular machinery and conditions for plaque formation. Here we report a spatial-temporal map of plaque load in 5xFAD mouse spinal cord. We found that plaques started to appear at 11 weeks, then exhibited a time dependent increase and differential distribution along the cord. More plaques were found in cervical than other spinal levels at all time points examined. Despite heavy plaque load at 6 months, the number of cervical motor neurons in 5xFAD mice is comparable to wild type littermates. On detailed microscopic examination, fine beta amyloid-containing and beta sheet-rich thread-like structures were found in the peri-axonal space of many axons. Importantly, these novel structures appear before any plaque deposits are visible in young mice spinal cord and they co-localize with axonal swellings at later stages, suggesting that these thread-like structures might represent the initial stages of plaque formation, and could play a role in axonal damage. Additionally, we were able to demonstrate increasing myelinopathy in aged 5xFAD mouse spinal cord using the lipid probe Nile Red with high resolution. Collectively, we found significant amyloid pathology in grey and white matter of the 5xFAD mouse spinal cord which indicates that this structure maybe a useful platform to study mechanisms of Alzheimer’s pathology and disease progression.

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

“…Within the spinal cord, extra‐cellular plaques develop in the gray matter, especially within the cervical division. Spheroids of aggregated Aβ also develop within axons of descending motor neurons, which is accompanied by peri‐axonal Aβ threads and abnormal swelling of myelin, likely leading to impaired axonal transport and neurotransmission . Interestingly, extra‐cellular plaques are not observed in peripheral nerves or neuromuscular junctions, nor are there functional impairments in the ability for motor nerves to drive muscular output, suggesting impairment is limited to the CNS .…”

“…Previous studies with 5xFAD mice have shown reduced body weight, along with impairments in motor coordination, balance, grip strength and gait beginning between 9 and 12 months of age . These motor impairments are thought to be due to the development of Aβ‐related pathology within the pyramidal and extra‐pyramidal motor systems of the brain and spinal cord, rather than dysfunction within the peripheral nervous system …”

“…22,24,25 These motor impairments are thought to be due to the development of Aβ-related pathology within the pyramidal and extra-pyramidal motor systems of the brain and spinal cord, rather than dysfunction within the peripheral nervous system. 22,24,26 The development of age-related motor dysfunction in 5xFAD mice may be modulated by background genes and sex. Sex differences have been shown in the lifespan 27 and in the severity of diseaserelated phenotypes in AD mouse models.…”

Unsuspected Involvement of Spinal Cord in Alzheimer Disease

“…On the other hand, given that we have also demonstrated that spinal cord features are independent of brain volumes, it cannot be excluded that alterations in spinal cord morphometric measurements (CSA and CSV) in AD are the result of primary retrogenesis linked to myelin and axonal pathology. It is indeed very significant that a recent study of another animal model of AD (the 5xFAD) shows amyloid plaques accumulation in the spinal cord tissue, with a particular concentration at cervical level and a time-dependent accumulation that starts 11 weeks from onset; interestingly, the same study found independent and extensive myelopathy, while the motoneurons count at 6 months was not altered compared to the wild type (Chu et al, 2017). While, we cannot be conclusive on the mechanisms of spinal cord atrophy in AD, our results are intriguing and calling for larger studies of prodromic subjects to be followed over time; such studies would also confirm whether the suggestion that the motor system (neocortex, cerebellum and spinal cord) is affected even before the cognitive one can be substantiated, or whether the spinal cord is following similar pathophysiological global changes as brain structures (Agosta et al, 2010;Albers et al, 2015;Toniolo et al, 2018).…”

“…Post-mortem histopathology has indicated that phosphorylated tau tangles are present in high proportion in the cervical spinal cord of AD cases compared to healthy subjects (Dugger et al, 2013). This is also supported by studies in different animal models of AD where pathological changes are demonstrated in the spinal cord as well as the brain (Yuan et al, 2013;Chu et al, 2017). Therefore, it is important to understand first of all whether the spinal cord plays a part in this disease and to understand how significant its involvement is.…”