Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice

Abstract

Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. In addition to the presence of cortical senile plaques and neurofibrillary tangles, AD is characterized at autopsy by extensive degeneration of brainstem locus coeruleus (LC) neurons that provide noradrenergic innervation to cortical neuropil, together with relative stability of dopaminergic neuron number in substantia nigra (SN) and ventral tegmental area (VTA). The present study used design-based stereological methods to assess catecholaminergic neuronal loss in brains of double transgenic female mice that co-express two human mutations associated with familial AD, amyloid precursor protein (APP(swe)) and presenilin-1 (PS1(DeltaE9)). Mice were analyzed at two age groups, 3-6 months and 16-23 months, when deposition of AD-type beta-amyloid (Abeta) plaques occurs in cortical brain regions. Blocks of brain tissue containing the noradrenergic LC nucleus and two nuclei of dopaminergic neurons, the SN and VTA, were sectioned and sampled in a systematic-random manner and immunostained for tyrosine hydroxylase (TH), a specific marker for catecholaminergic neurons. Using the optical fractionator method we found a 24% reduction in the total number of TH-positive neurons in LC with no changes in SN-VTA of aged dtg APP/PS1 mice compared with non-transgenic controls. No significant differences were observed in numbers of TH-positive neurons in LC or SN-VTA in brains of young female dtg APP/PS1 mice compared to their age-matched controls. The findings of selective neurodegeneration of LC neurons in the brains of aged female dtg APP/PS1 mice mimic the neuropathology in the brains of AD patients at autopsy. These findings support the use of murine models of Abeta deposition to develop novel strategies for the therapeutic management of patients afflicted with AD.

Figure 1

Low magnification (4X) photomicrographs of TH-positive neurons in (A) LC from non-tg littermate controls aged 3–6 mos; (B) LC from dtg APP/PS1 mice aged 16–23 mos; (C) SN-VTA from non-tg littermate controls aged 3–6 mos; (D) SN-VTA from dtg APP/PS1 mice aged 16–23 mos. Insert: High magnification (60 x) with an optical disector of TH positive cells. Scale bar= 50μm

Figure 2

Mean (SEM) total number of TH-positive neurons in LC of 16–23 month old female APP/PS1 mice (n=7) and age-matched non-tg littermate controls. (n=9); p<0.01.

Figure 3

Mean (SEM) total number of TH-positive neurons in LC of 3–6 month old female APP/PS1 mice (n=7) and age-matched non-tg littermate controls (n=9).

Figure 4

Mean (SEM) total number of TH-positive neurons in SN-VTA of 16–23 month old female APP/PS1 mice (n=7) and age-matched non-tg littermate controls. (n=9).