APP transgenic mice displayed region-specific alterations in hippocampal noradrenergic fiber density that followed distinct age-related trajectories, and these alterations were not associated with amyloid-β plaque load and occurred in the absence of neuronal loss or Aβ plaques in the locus coeruleus.
Key Findings
Results
APP transgenic mice showed region-specific alterations in hippocampal noradrenergic fiber density compared to age-matched wild-type controls, with distinct age-related trajectories across hippocampal subregions.
Noradrenergic fiber density was evaluated at 2, 6, 12, and 20 months of age in APP mice expressing mutant human amyloid precursor protein and nontransgenic wild-type littermate controls.
Alterations in noradrenergic innervation were region-specific, meaning different hippocampal subregions showed different patterns and trajectories of change.
The study assessed cortex and multiple subregions of the hippocampus to capture spatial distribution of noradrenergic axonal projections.
Results
Alterations in noradrenergic innervation in APP mice were not associated with the extent of amyloid-β plaque load in the hippocampus or cortex.
The dissociation between noradrenergic fiber density changes and Aβ plaque burden suggests that noradrenergic alterations are not simply a consequence of local amyloid deposition.
Both hippocampal and cortical Aβ plaque load were examined in relation to noradrenergic fiber density measures.
This finding implies that noradrenergic innervation changes may precede or occur independently of plaque accumulation in these regions.
Results
Noradrenergic innervation changes in APP mice occurred in the absence of neuronal loss or Aβ plaques in the locus coeruleus.
The LC was examined for neuronal loss and Aβ plaque pathology in APP transgenic mice.
No significant neuronal loss was detected in the LC of APP mice at the ages studied.
No Aβ plaques were found in the LC, indicating that LC axonal projection changes in target regions occurred without overt LC somatic pathology.
Results
APP transgenic mice showed subtle decreases in cortical noradrenergic fiber density compared to age-matched controls.
Cortical noradrenergic fiber density reductions were described as subtle relative to the more pronounced region-specific hippocampal alterations.
The cortical changes were evaluated across the same four age time points (2, 6, 12, and 20 months).
Cortical alterations were less spatiotemporally complex compared to hippocampal subregion-specific changes.
Results
Wild-type mice showed subtle but robust alterations in noradrenergic fiber density across the brain between 2 and 20 months of age, indicating normal aging affects noradrenergic innervation.
Age-related changes in noradrenergic fiber density were observed in nontransgenic wild-type littermate controls across the 2–20 month age range.
These changes were described as 'subtle but robust,' suggesting statistically reliable differences across age groups even in the absence of disease-related transgene expression.
The finding establishes that normal aging itself contributes to alterations in noradrenergic innervation independent of APP-related pathology.
Background
The locus coeruleus is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease, motivating investigation of its projections in mouse models.
LC neuronal loss and associated reductions in norepinephrine in the brain have been postulated to play a key role in AD pathophysiology.
Norepinephrine plays critical roles in modulating arousal and attention and has anti-inflammatory and neuroprotective actions.
Prior to this study, the time course and spatial distribution of alterations in noradrenergic LC projections were described as 'not fully understood.'
Results
The study found spatiotemporally complex alterations in noradrenergic innervation across both normal aging and disease progression in APP mice.
Complexity was both spatial (varying across brain regions and hippocampal subregions) and temporal (varying across the four age time points examined).
The pattern of changes differed between APP transgenic and wild-type mice, and also differed among hippocampal subregions within APP mice.
The results reveal that characterizing noradrenergic innervation requires consideration of both region-specific and age-specific factors.
Hernandez N, Silva-Pérez M, Chin J. (2026). Noradrenergic innervation across brain regions is altered by aging and by disease progression in a mouse model of Alzheimer's disease neuropathology.. PloS one. https://doi.org/10.1371/journal.pone.0340611