Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Aβ production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

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Post-anesthetic equine myelopathy: characterization of neuronal reaction and axonal injury using beta-amyloid precursor protein immunohistochemistry

10.21203/rs.3.rs-27403/v1 ◽

2020 ◽

Author(s):

Jessica S Fortin ◽

Joanne Kramer ◽

Alex D Bukoski ◽

Dae Y Kim

Keyword(s):

Spinal Cord ◽

Amyloid Precursor Protein ◽

Axonal Transport ◽

Axonal Injury ◽

Beta Amyloid ◽

Transport Proteins ◽

Precursor Protein ◽

Sensory Function ◽

Fast Axonal Transport ◽

Post Surgery

Abstract A 2-year-old female Clydesdale horse was anesthetized in dorsal recumbency for an elective surgical procedure to treat osteochondritis dissecans involving the intermediate ridge of the right tibia. Following surgery, the horse lost motor and sensory function in the hind limbs and was unable to stand. The status deteriorated and the horse was euthanized 20 h post-surgery. Histopathologic examination revealed mild to moderate acute myelopathy of the spinal cord between T14 and S3. The lesions were bilateral, with one side being slightly more affected, and more severe in the distal lumbar and sacral spinal cord segments. Immunohistochemistry for beta-amyloid precursor protein (β-APP) was compared to other fast axonal transport proteins such as neurofilament heavy protein, synaptophysin, and ubiquitin. In the presented case, the β-APP immunohistochemistry revealed positively-labeled, multiple, segmentally-swollen axons (axonal bulbs) and rarely neurons. The positively-stained areas overlapped with the lesions seen on HE stained slides including areas in which changes were poorly discernible by routine histologic exam. Amongst the fast axonal transport proteins detected via immunohistochemistry, β-APP was considered adequate to use as a potential sensitive biomarker for axonal injury in this case of post-anesthetic myelopathy. β-APP immunohistochemistry may be a useful tool to study and diagnose axonal injuries of the central and peripheral nervous system in veterinary medicine.

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