Spinal cord injury across the World is one of the prominent causes of disability in military as well as the civilians for which no suitable therapeutic measures are available so far (Avila et al., 2021, Furlan et al., 2020, Hersh et al., 2022). Direct physical trauma to the spinal cord and associated secondary injury mechanisms lead to microhemorrhages, disruption of the blood–spinal cord barrier (BSCB), edema formation and cell injury (Sharma, 2004, Sharma, 2005, Sharma and Westman, 2004, Stålberg et al., 1998, Winkler et al., 1998) leading to functional disability. Thus, to expand our knowledge about spinal cord injury pathophysiology and consequences of disability require further investigation in order explore novel strategies to restore functions in victims. Our laboratory is engaged to find suitable therapeutic measures using nanodelivery of drugs and neutralizing endogenous neurotoxic agents using monoclonal antibodies in spinal cord injury to achieve neuroprotection and functional rehabilitation of patients (Sharma and Sharma, 2012, Sharma, 2011, Sharma and Sharma, 2008, Sharma and Sharma, 2012a, Sharma and Sharma, 2013, Sharma and Sharma, 2023, Tian et al., 2012). However, further studies are needed to find out other neurotoxic markers in spinal cord following injury that leads to pathological disruption of sensory motor functions in trauma patients.

Several reports suggest that trauma to the brain is one of the risk factors for developing Alzheimer’s disease (Brett et al., 2022, Dams-O′Connor et al., 2016, Djordjevic et al., 2016, Sivanandam and Thakur, 2012). However, information about development of Alzheimer’s disease following spinal cord injury is not well characterized (Guo et al., 2017, Kelleher and Shen, 2017, Kobayashi et al., 2010, Li et al., 1995, Muñoz et al., 2022). In a study reported by Guo et al., (Guo et al., 2017) the levels of amyloid beta peptide in the cerebrospinal fluid and in brain was measured using ELISA after spinal cord contusion model with mild or severe injury. These results show significant correlation with severity of spinal cord injury with elevation of amyloid beta peptide in the CSF and in brain following 3rd to 28th days (Guo et al., 2017). This suggests that precipitation of Alzheimer’s disease pathology could also occur after spinal cord injury. Kobayashi et al., (Kobayashi et al., 2010) examined upregulation of presenilin 1 (PS1), amyloid precursor protein (APP) and amyloid beta peptide (AβP) after hemisection of the spinal cord in perifocal segments. Their results show that hemisection of spinal cord results in significant elevation of PS1, APP as well as AβP in the spinal cord about 1 mm away from the lesion 24 h after trauma (Kobayashi et al., 2010). PS1 mutation is seen in Alzheimer’s disease, spastic paraplegia and spinal cord atrophy (Kelleher and Shen, 2017, Muñoz et al., 2022) thus their results suggest an important link between spinal cord injury and Alzheimer’s disease (Kelleher and Shen, 2017, Kobayashi et al., 2010, Muñoz et al., 2022). On the other hand, when transgenic mice model for Alzheimer’s disease was used to study the effects of spinal cord transection on axonal damage leading to upregulation of APP and its product AβP in spinal cord the results showed an opposite effect (Yuan, Yang, et al., 2020). Thus, the lesion area showed upregulation of CD68 indicating activation of microglia but the APP and AβP burden is reduced in the traumatized zone in transgenic mice (Yuan, Yang, et al., 2020). Another study showed that in transgenic Alzheimer’s mice trauma to the spinal cord results in deposition of AβP from vascular origin in the dorsal horn and parenchymal origin in the ventral horn indicating difference in origin of AβP plaque formation (Yuan, Liu, et al., 2020). Another study of compression induced spinal cord trauma showed accumulation of APP in axons as early as 4 h after trauma and increased gradually over the 9th day in rats with compression injury. The magnitude and severity of APP accumulation is related to the severity of compression injury to the cord (Li et al., 1995). These studies indicate alterations of Alzheimer’s disease biomarkers following spinal cord injury.

Apart from amyloid beta peptide, p-tau is another hallmark of Alzheimer’s disease (Ossenkoppele, van der Kant, & Hansson, 2022). Few studies report elevation of p-tau following spinal cord injury as well (Caprelli et al., 2018, Nakhjiri et al., 2022, Nakhjiri et al., 2020). Nakhjiri et al. (2022) reports significant increase in tau protein after spinal cord injury that is spread to the brain over time and induce functional deficit. The magnitude and severity of spinal cord injury correlates with the degree of tau spread and intensity into the spinal cord as well as the brain. Treatment with antibodies to tau significantly reduced locomotor deficit and other functional parameters following spinal cord injury in mouse model (Nakhjiri et al., 2022). These authors in another study clearly show that phosphorylated tau spread over the spinal cord, CSF and in brain after a focal spinal cord trauma and lead to neurodegeneration in the brain and spinal cord. This effect is attenuated by p-tau antibodies indicating a putative role of p-tau antibody for clinical therapy in spinal cord injury victims (Nakhjiri et al., 2020). Caprelli et al. (2018) using compact compression model of spinal cord injury in rats showed elevation of p-tau within the spinal cord of both rostral and caudal segments up to 5000 µm always from the lesion sites. Increased serum and CSF tau was also seen after the spinal cord injury of 24 h period indicating that p-tau could be a biomarker of spinal cord injury (Caprelli et al., 2018).

These observations clearly show that spinal cord injury is also a potential risk factor in Alzheimer’s disease pathophysiology affecting brain neurodegeneration as well. Thus, further studies are needed to expand Alzheimer’s disease pathology following spinal cord injury, a feature that is currently being examined in our laboratory.

Spinal cord injury activates astrocytes, microglia and neuroinflammatory responses immediately after trauma (Lund, Clausen, Brambilla, & Lambertsen, 2023). Neuroinflammation cascade after spinal cord injury initiates recruitment of immune cells such macrophages at the site of injury (Kisucká, Bimbová, Bačová, Gálik, & Lukáčová, 2021). Although activation of microglia and macrophages at the site of injury is primarily due to clear the debris and restore normal situation but these response also induces neuroinflammation (Lukacova et al., 2021, Lund et al., 2023). One of the neuroinflammatory cytokine is tumor necrosis factor alpha (TNF-α) that is enhanced following spinal cord injury (Wang, Nuttin, Heremans, Dom, & Gybels, 1996). Thus, attenuating or neutralizing effects of TNF-α in spinal cord injury using monoclonal antibodies over the traumatized spinal cord induces neuroprotection (Sharma, 2008, Sharma and Westman, 2003, Sharma et al., 2009). Thus, further studies using a combination of monoclonal antibodies (mAbs) to TNF-α together with amyloid beta peptide and p-tau may induce superior neuroprotection spinal cord injury, a feature requires further investigation (see below).

Spinal cord is considered as an extension of the brain as well as conversely, the brain is considered by some as an extension of the spinal cord (Sharma, 2008, Sharma and Westman, 2003, Sharma et al., 2009, Windle, 1980). Thus, spinal cord injury affects brain dysfunction including dementia, depression and neuroinflammation (Li et al., 2020, Sharma, 2008, Sharma and Westman, 2003, Sharma et al., 2009, Windle, 1980). Although, cognitive deficit is supposed to be a function of brain injury and so far influence of spinal cord trauma is not well considered on brain dysfunction. However, there is a continuation of neural network in both directions between brain and the spinal cord (Windle, 1980) there are reasons to believe that spinal cord injury affects brain dysfunction. This is further supported by the clinical observations in patients of spinal cord injury showing cognitive and emotional deficits in more than 60% of cases (Davidoff et al., 1992, Dowler et al., 1997, Lazzaro et al., 2013, Richards et al., 1988, Windle, 1980). In many patients cognitive deficits is present in spinal cord injury without any traumatic brain damage (Huang et al., 2017, Murray et al., 2007). Spinal cord injury patients often show attention deficits, lack of concentration, memory dysfunction and learning disabilities (Roth et al., 1989). These studies support the idea that spinal cord injury contributes to cognitive deficits.

Apart from cognitive deficits, spinal cord injury patients exhibit mood disturbances, depression anxiety and symptoms similar to the posttraumatic stress disorders (PTSD) (Craig et al., 2015, Post and van Leeuwen, 2012). The observed pathophysiological changes in the brain following spinal cord injury are limited to the localized brain regions involving sensorimotor pathways. Imaging studies show that spinal cord injury could results in extensive long-term reorganization within the cerebral cortex (Migliorini et al., 2009, Shin et al., 2012). This is further evident with the findings that complete thoracic injury results in loss of gray matter volume in the primary motor cortex exhibiting neuronal loss (Wrigley et al., 2009). These observations suggest that spinal cord injury could impair cortical and subcortical neuronal networks involved in the information processing system (Lazzaro et al., 2013). Observation of enlarged cerebral ventricles and increased CSF volume leading to enhance neurodegenerative processes in spinal cord injury further supports involvement of brain in these patients (Seif, Ziegler, & Freund, 2018). These clinical observations show widespread alterations in the brain after spinal cord injury affecting neurological dysfunction (Li et al., 2020).