Cholinergic neuropathology in a mouse model of Alzheimer's disease.

Transgenic mice overexpressing mutant human amyloid precursor protein (PDAPP mice) develop several Alzheimer's disease (AD)-like lesions including an age-related accumulation of amyloid-beta (Abeta)-containing neuritic plaques. Although aged, heterozygous PDAPP mice also exhibit synaptic and glial cell changes characteristic of AD pathology, no evidence of widespread neuronal loss has been observed. The present study sought to determine whether homozygous PDAPP mice, which express very high levels of Abeta peptide, exhibit AD-like cholinergic degenerative changes, and whether the changes parallel the deposition of Abeta plaques. Mice were examined at 2 and 4 months and at 1 and 2 years of age. There was an age-related increase in the density of Abeta plaques in the cortex and hippocampus of the PDAPP animals; at 4 months of age there were very few plaques, and at 2 years there was a very high density of plaques. There was an age-related reduction in the density of cholinergic nerve terminals in the cerebral cortex; at 2 months there was a normal density of nerve terminals, but as early as age 4 months there was an approximately 50% reduction. However, at age 2 years there was no difference in the number or size of basal forebrain cholinergic somata compared with 2-month-old PDAPP mice. These data indicated that the homozygous PDAPP mouse exhibits cholinergic nerve terminal degenerative pathology and that the cortical neurodegenerative changes occur before the deposition of Abeta-containing neuritic plaques.

German DC ，Yazdani U ，Speciale SG ，Pasbakhsh P ，Games D ，Liang CL ... -  《JOURNAL OF COMPARATIVE NEUROLOGY》

Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer's disease.

Aucoin JS ，Jiang P ，Aznavour N ，Tong XK ，Buttini M ，Descarries L ，Hamel E ... -  《-》

The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.

Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress.

German DC ，Nelson O ，Liang F ，Liang CL ，Games D ... -  《JOURNAL OF COMPARATIVE NEUROLOGY》

Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway.

Cholinergic basal forebrain (CBF) projection systems are defective in late Alzheimer's disease (AD). We examined the brains of 12-month-old singly and doubly transgenic mice overexpressing mutant amyloid precursor protein (APP(swe)) and/or presenilin-1 (PS1(M146L)) to investigate the effects of these AD-related genes on plaque and tangle pathology, astrocytic expression, and the CBF projection system. Two types of beta-amyloid (Abeta)-immunoreactive (ir) plaques were observed: type 1 were darkly stained oval and elongated deposits of Abeta, and type 2 were diffuse plaques containing amyloid fibrils. APP(swe) and PS1(M146L) mouse brains contained some type 1 plaques, while the doubly transgenic (APP(swe)/PS1(M146L)) mice displayed a greater abundance of types 1 and 2 plaques. Sections immunostained for the p75 NGF receptor (p75(NTR)) revealed circular patches scattered throughout the cortex and hippocampus of the APP(swe)/PS1(M146L) mice that contained Abeta, were innervated by p75(NTR)-ir neurites, but displayed virtually no immunopositive neurons. Tau pathology was not seen in any transgenic genotype, although a massive glial response occurred in the APP(swe)/PS1(M146L) mice associated with amyloid plaques. Stereology revealed a significant increase in p75(NTR)-ir medial septal neurons in the APP(swe) and PS1(M146L) singly transgenic mice compared to the APP(swe)/PS1(M146L) mice. No differences in size or optical density of p75(NTR)-ir neurons were observed in these three mutants. p75(NTR)-ir fibers in hippocampus and cortex were more pronounced in the APP(swe) and PS1(M146L) mice, while the APP(swe)/PS1(M146L) mice showed the least p75(NTR)-ir fiber staining. These findings suggest a neurotrophic role for mutant APP and PS1 upon cholinergic hippocampal projection neurons at 12 months of age.

Jaffar S ，Counts SE ，Ma SY ，Dadko E ，Gordon MN ，Morgan D ，Mufson EJ ... -  《EXPERIMENTAL NEUROLOGY》

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease.

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies.

Donovan MH ，Yazdani U ，Norris RD ，Games D ，German DC ，Eisch AJ ... -  《JOURNAL OF COMPARATIVE NEUROLOGY》