Age-related loss of noradrenergic neurons in the brains of triple transgenic mice

Abstract

Microscopic findings in Alzheimer's disease (AD) at autopsy include a wide cortical distribution of beta amyloid (Aβ)-containing plaques and diminished numbers of pyramidal neurons in CA1 of hippocampus and tyrosine hydroxylase-positive (TH+) neurons in the locus coeruleus (LC). To better understand the neuropathology underlying cognitive decline in AD, we analyzed the AD-type neuropathology in brains of triple transgenic (3×Tg) mice harboring mutations for APP(swe), PS1(M146V), and tau(P301L). Histochemical and immunohistochemical staining and computerized stereology were carried out in age-matched young, early middle age, and late middle age 3×Tg mice. The 3×Tg mice showed an intracellular Aβ deposition in subiculum and CA1 pyramidal neurons and an extracellular distribution of amyloid plaques specifically in the subiculum of hippocampal formation and in neocortical layer V. The 3×Tg mice also showed an age-related loss of TH+ neurons in LC, with a loss of 37% of these neurons at 15 months of age. There was no loss of CA1 neurons at any age examined. Reduced AD-type neuropathology in CA1 of 3×Tg mice suggests a possible neuroprotective role for high intracellular-to-extracellular ratios of insoluble Aβ deposits. Understanding the neurobiology of this apparent neuroprotection could lead to an improved understanding of age-related cognitive function in general, and the development of novel strategies for the therapeutic management of AD patients.

Fig. 1

Distribution of Aβ and phospho-tau at the hippocampal formation in the 3×Tg mouse model. a Low-magnification (×4) images of Aβ-40 (left column), PHF-tau (middle column), and combined staining (right column) of 3×Tg mice at 8 months (top row), 12 months (middle row), and 15 months of age (bottom row). b High-magnification (×60) images from a 15-month-old mouse

Fig. 2

Preferential accumulation of extracellular Aβ in cortical layer V. A low-magnification (×4) comparison of Aβ deposition in cortex of 13-month-old dtg (left) and 12-month-old 3×Tg (right) mice shows that while Aβ deposits are found in all layers of cortex of dtg mice, they are found only in layer V of 3×Tg mice

Fig. 3

Age-dependent loss of norepinephrine neurons in the 3×Tg mice. Low-magnification (×4) image of TH staining in LC region of 3×Tg mice at 8 (a), 12 (b), and 15 months (c). d Stereological analysis carried out at high magnification (×60) revealed an age-dependent loss of TH-ir neurons in LC of 3×Tg mice (*p < 0.05)

Fig. 4

Accumulation of extracellular Aβ with age in the hippocampus. Low-magnification (×4) image of Congo red staining in hippocampus of 3×Tg mice at 8 (a), 12 (b), and 15 months (c). d Stereological analysis revealed an age-dependent accumulation of extracellular deposits in 3×Tg mice (*p < 0.05)

Fig. 5

Sparing of CA1 neurons in 3×Tg mice. Low-magnification (×4) image of Nissl staining in CA1 subregion of 3×Tg mice at 8 (a), 12 (b), and 15 months (c). d Stereological analysis revealed no relationship between age and the number of CA1 pyramidal neurons