Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice

NEUROBIOLOGY OF DISEASE

卷:41

Article

Perez, Sylvia E.¹  He, Bin¹  Muhammad, Nadeem¹  Oh, Kwang-Jin¹  Fahnestock, Margaret²  Ikonomovic, Milos D.^3,4,5  Mufson, Elliott J.¹ 

[1] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[2] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada

[3] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA

[4] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

[5] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA

关键词: Alzheimer's disease;    Amyloid;    Cholinergic;    Nerve growth factor;    ChAT;    proNGF;    p75(NTR);    Transgenic mice;    TrkA;    Aging;   

DOI  :  10.1016/j.nbd.2010.10.002

来源: Elsevier

【 摘 要 】

The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However. nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying A beta, plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2-4 months), middle-aged (13-15 months) and old (18-20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal-subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75(NTR) protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by A beta plaque pathology. (C) 2010 Elsevier Inc. All rights reserved.

【 授权许可】

Free