• Kathleen C Maigler, Trevor J Buhr, Christopher S Park, Steven A Miller, Dorothy A Kozlowski, and Robert A Marr.
• Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
• J. Neurotrauma. 2021 Mar 1; 38 (5): 665-676.

AbstractTraumatic brain injury (TBI) increases the risk for dementias including Alzheimer's disease (AD) and chronic traumatic encephalopathy. Further, both human and animal model data indicate that amyloid-beta (Aβ) peptide accumulation and its production machinery are upregulated by TBI. Considering the clear link between chronic Aβ elevation and AD as well as tau pathology, the role(s) of Aβ in TBI is of high importance. Endopeptidases, including the neprilysin (NEP)-like enzymes, are key mediators of Aβ clearance and may affect susceptibility to pathology post-TBI. Here, we use a "humanized" mouse model of Aβ production, which expresses normal human amyloid-beta precursor protein (APP) under its natural transcriptional regulation and exposed them to a more clinically relevant repeated closed-head TBI paradigm. These transgenic mice also were crossed with mice deficient for the Aβ degrading enzymes NEP or NEP2 to assess models of reduced cerebral Aβ clearance in our TBI model. Our results show that the presence of the human form of Aβ did not exacerbate motor (Rotarod) and spatial learning/memory deficits (Morris water maze) post-injuries, while potentially reduced anxiety (Open Field) was observed. NEP and NEP2 deficiency also did not exacerbate these deficits post-injuries and was associated with protection from motor (NEP and NEP2) and spatial learning/memory deficits (NEP only). These data suggest that normally regulated expression of wild-type human APP/Aβ does not contribute to deficits acutely after TBI and may be protective at this stage of injury.

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