Research ReportFemales exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model
Introduction
Alzheimer's disease (AD) is a neurodegenerative disease that is the most common form of dementia. Only a small portion (< 1%) of cases have known genetic causes, while the majority of AD cases are sporadic (Cummings, 2004). The most significant non-genetic risk factor for AD is age; the risk of AD doubles between the age groups of 65–70 and 70–74. In addition to age, various factors, such as medical history (head injury, stroke, hypertension, hypercholesterolemia, stress, etc.), life style (diet, lack of exercise, alcohol consumption, smoking, etc) and education, may be associated with AD (McDowell, 2001). Epidemiological studies also indicate that women have a higher risk of AD (Brookmeyer et al., 1998) even after adjusting for age (Hy and Keller, 2000). The precise cause of the higher risk of AD in women is unknown.
The pathological hallmarks of AD are amyloid plaques in the extracellular space and intraneuronal neurofibrillary tangles (Hyman, 1997). Amyloid beta (Abeta), the primary component of amyloid plaques, is generated from the amyloid precursor protein (APP) by sequential proteolytic cleavage at the beta and gamma sites (Hardy and Selkoe, 2002). Freshly generated Abeta forms oligomers on and within neurons (Walsh et al., 2000) and compromises hippocampal long-term potentiation in vivo (Walsh et al., 2002). Neurofibrillary tangles are composed of hyperphosphorylated tau, a neuronal microtubule-associated protein. Phosphorylation of tau regulates its ability to promote microtubule assembly (Lindwall and Cole, 1984); hyperphosphorylation interferes with the normal biological functions of tau by reducing its ability to bind to and stabilize microtubules (Trojanowski and Lee, 1995). All genetic mutations that cause familial AD are linked to the Abeta cascade, while tau mutations are associated with AD and several other forms of dementia including frontotemporal dementia and progressive supranuclear palsy (Hardy and Selkoe, 2002). The clinical progression of AD is closely related to tau pathology (Braak and Braak, 1995). In animal models, modulation of Abeta or tau cascades alter pathology and influence cognitive function (Barten et al., 2005, SantaCruz et al., 2005).
To investigate the mechanisms of these pathological events and explore therapeutic strategies, various lines of transgenic mice have been created (McGowan et al., 2006). Overexpression of mutant APP elevates Abeta production leading to plaque formation (Games et al., 1995, Hsiao et al., 1996). Overexpression of mutant presenilin (PS)-1 elevates the level of endogenous Abeta slightly, but does not induce Abeta plaque deposition (Duff et al., 1996). Mice obtained by crossing APP and PS-1 transgenic mice show dramatically accelerated Abeta pathology (Holcomb et al., 1998) associated with oxidative stress and neuroinflammation (Matsuoka et al., 2001a, Matsuoka et al., 2001b). Overexpression of mutant tau causes hyperphosphorylation and tangle formation (Lewis et al., 2000). In many tau transgenic mice, tauopathy is more evident in the brainstem and spinal cord and is associated with motor dysfunction. Some tau transgenic mice, including the one used in this study, show tau pathology in the brain along with cognitive impairment (Ramsden et al., 2005).
Currently available AD mouse models are well-characterized, but the effects of gender on Abeta and tau pathology in animal models have not been carefully examined. Previously, gender differences have been studied in Tg2576 APP transgenic mice, which develop Abeta, but not tau pathology. In that study, female mice showed more histologically-determined Abeta plaques at 15 and 19 months of age and ELISA-quantified Abeta 1–40 (but not Abeta 1–42) load at 15 months of age (Callahan et al., 2001). Mice at these two time points bear Abeta plaques; the effect of gender at the pre-plaque stage was not evaluated. Abeta and tau pathology influence each other, but gender influences on the co-occurrence of these two aspects of AD pathology have not been examined. In this study, we examined the progression of AD-related pathology in male and female mice during the course of their lifespan using transgenic mice which develop both Abeta and tau pathology. In addition, we also investigated the progression of Abeta pathology in male mice at additional age points.
Section snippets
Soluble and total Abeta 1–40 and 1–42 are increased with aging after plaque formation
Our Abeta ELISAs were composed of N and C-terminus end-specific antibodies to quantify full-length Abeta 1–40 and 1–42 (Horikoshi et al., 2004). Both the Abeta 1–40 and 1–42 ELISAs provide linear (r2 > 0.99) standard curves over the range of 1–800 fmol/ml (pM). In this study, results from multiple plates needed to be combined; therefore, to assure quality control, we used a higher cut-off, 10 fmol/ml, which is equivalent to 220 and 6500 fmol/g tissue in diethylamine (DEA) and formic acid (FA)
Discussion
Epidemiological studies indicate that women have a higher risk of AD even after adjustment for age (Brookmeyer et al., 1998), the most important risk factor for AD (Hy and Keller, 2000). Transgenic mice expressing pathogenic genes of AD develop Abeta and/or tau pathology (McGowan et al., 2006); however, previous studies of AD transgenic mouse models have not necessarily reflected a consistent gender difference. In Tg2576 mice, the Abeta 1–40 level has been reported to be higher in females than
Animals and sampling
We used 3xTg-AD mice (Oddo et al., 2003) generated by co-microinjection of mutant APP (K670M/N671L) and tau (P301L) transgenes under the control of Thy 1.2 promoter into mutant PS-1 (M146V) knock-in mice (Guo et al., 1999). 3xTg-AD mice were created by a group at the University California, Irvine, in collaboration with a group at the National Institute on Aging. The colony was established at Georgetown University using breeding pairs provided by the National Institute on Aging after
Acknowledgments
We thank Ms. Hibiki Takenouchi, Department of Neurology, Georgetown University, for her technical assistance. Ms. Hibiki is a visiting student from Shiga University of Medical Science, Japan. We also thank Dr. Mary Ann Ottinger, University of Maryland, and Drs. Donna M. Barten and Margi Goldstein, Bristol-Myers Squibb for sharing their findings in the 3xTg-AD mouse colony maintained at their institute. Antibodies used for Abeta ELISA and Abeta immunostaining were generously provided by Dr.
References (61)
- et al.
Staging of Alzheimer's disease-related neurofibrillary changes
Neurobiol. Aging
(1995) - et al.
Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders
Neurobiol. Aging
(2005) - et al.
Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles
Am. J. Pathol.
(2007) - et al.
Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice
Am. J. Pathol.
(2001) - et al.
Post-menopausal estrogen deprivation and Alzheimer's disease
Exp. Gerontol.
(2000) - et al.
Development of Abeta terminal end-specific antibodies and sensitive ELISA for Abeta variant
Biochem. Biophys. Res. Commun.
(2004) - et al.
Estrogen regulates neprilysin activity in rat brain
Neurosci. Lett.
(2004) The neuropathological diagnosis of Alzheimer's disease: clinical–pathological studies
Neurobiol. Aging
(1997)- et al.
Metabolism of amyloid-beta peptide and Alzheimer's disease
Pharmacol. Ther.
(2005) - et al.
Epitopes that span the tau molecule are shared with paired helical filaments
Neuron
(1988)
Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice
Cell
Phosphorylation affects the ability of tau protein to promote microtubule assembly
J. Biol. Chem.
Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease
Neuroscience
Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease
Am. J. Pathol.
A decade of modeling Alzheimer's disease in transgenic mice
Trends Genet.
Hippocampal synthesis of estrogens and androgens which are paracrine modulators of synaptic plasticity: synaptocrinology
Neuroscience
Triple-transgenic model of Alzheimer's disease with plaques and tangles. Intracellular abeta and synaptic dysfunction
Neuron
Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
Neuron
Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease
Lancet
Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor
J. Pharmacol. Exp. Ther.
The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region
EMBO J.
Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Am. J. Public Health
Alzheimer's disease
N. Engl. J. Med.
Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1
Nature
Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease
Arch. Neurol.
Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein
Nature
Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils
Science
Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer's disease
Endocrinology
A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis
Proc. Natl. Acad. Sci. U. S. A.
Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice
Nat. Med.
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