Amyloid plaque pathogenesis in 5XFAD mouse spinal cord: retrograde transneuronal modulation after peripheral nerve injury

Abstract

The spinal cord is composed of distinct neuronal groups with well-defined anatomic connections. In some transgenic models of Alzheimer’s disease (AD) amyloid plaques develop in this structure, although the underlying cellular mechanism remains elusive. We attempted to explore the origin, evolution and modulation of spinal β-amyloid (Aβ) deposition using transgenic mice harboring five familiar AD-related mutations (5XFAD) as an experiential model. Dystrophic neuritic elements with enhanced β-secretase-1 (BACE1) immunoreactivity (IR) appeared as early as 2 months of age, and increased with age up to 12 months examined in this study, mostly over the ventral horn (VH). Extracellular Aβ IR emerged and developed during this same period, site-specifically co-existing with BACE1-labeled neurites often in the vicinity of large VH neurons that expressed the mutant human APP. The BACE1-labled neurites almost invariably colocalized with β-amyloid precursor protein (APP) and synaptophysin, and frequently with the vesicular glutamate transporter-1 (VGLUT). Reduced IR for the neuronal specific nuclear antigen (NeuN) occurred in the VH by 12 months of age. In 8 month-old animals surviving 6 months after an unilateral sciatic nerve transection, there were significant increases of Aβ, BACE1 and VGLUT IR in the VN of the ipsilateral relative to contralateral lumbar spinal segments. These results suggest that extracellular Aβ deposition in 5XFAD mouse spinal cord relates to a progressive and amyloidogenic synaptic pathology largely involving presynaptic axon terminals from projection neurons in the brain. Spinal neuritic plaque formation is enhanced after peripheral axotomy, suggesting a retrograde transneuronal modulation on pathogenesis.

Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats

“…In human and transgenic animal brains with amyloid plaque pathology, BACE1 immunoreactivity is increased but preferentially localized to swollen and sprouting axonal terminals or axonal dystrophic neurites [33]–[35] [42]. In the present study, BACE1 labeling in both cerebral hemispheres in the PBS injected brains and the contralateral cerebrum in the LPS-injected animals exhibited the aforementioned normal distribution pattern (Figure 3(A) and Figure 3(B)).…”

“…Besides synaptic degeneration, axonal elements including presynaptic terminals undergo aberrant sprouting and dystrophic expansion [30]–[32]. Recent data from transgenic AD models, nonhuman primates and human subjects show that upregulation of the amyloidogenic proteins, especially the rate-limiting enzyme β -secretase-1 (BACE1), appears to be an molecular cascade tightly associated with axonal sprouting and dystrophy, suggestive of a driving role for amyloidogenic axonal pathology in plaque formation [33]–[35]. …”

Can BACE1 Inhibition Mitigate Early Axonal Pathology in Neurological Diseases?

“…BACE1 elevation appears to occur in the brain from a fairly early age among several plaque-forming transgenic AD models examined so far, including Tg2576, 2XFAD, 5XFAD, and 3xTgAD [10,11,35-37,39,66,67]. Importantly, the onset and evolution of typical neuritic plaques in the brain and spinal cord correlate with a progressive axon terminal pathology associated with BACE1 overexpression.…”

“…Besides BACE1, the abnormal axonal elements can also be co-labeled by antibodies against the transgenic AβPP, Aβ monomers or aggregates, and some specific neuronal phenotype markers. Extracellular Aβ deposits are absent from the small and isolated dystrophic axon terminals, but emerge and accumulate with the growth/expansion of the dystrophic neurites, especially as these neurites become rosette-like clusters [36,37,55,59, 62, 66-70] (Fig. 2A-D).…”

“…In epileptic 3×TgAD mice, plaque pathology is accelerated and enhanced in the hippocampal formation, limbic cortex, and amygdala relative to age-matched counterparts, regionally correlated with increased axonal sprouting and dystrophy [70]. Also in 3×TgAD mice, sciatic nerve axotomy facilitates neuritic dystrophy in parallel with increased plaque formation in the ventral horn of the lumber spinal segments, suggesting a retrograde modulation by the axonal injury on neuritic plaque pathogenesis around the somata of traumatized motor neurons [66]. …”