Decreased hippocampal cell proliferation correlates with increased expression of BMP4 in the APPswe/PS1DeltaE9 mouse model of Alzheimer's disease

Alterations in hippocampal cell proliferation have been identified in transgenic (tg) mouse models of Alzheimer's disease (AD); however, relatively little is known about the underlying mechanisms. Previously, we have demonstrated that endogenous level of BMP4 in the dentate gyrus (DG) affects hippocampal cell proliferation in a pentylentetrazol kindling-induced epilepsy model. In the present study, we evaluated hippocampal cell proliferation and BMP4 mRNA level in the APPswe/PS1DeltaE9 tg mouse, a well-established mouse model in which coexpression of familial AD-linked APP "Swedish" (APPswe) and PS1DeltaE9 polypeptide variants leads to Abeta deposition throughout the hippocampus and cortex. The number of bromodeoxyuridine (BrdU)-labeled cells in the DG subgranular zone (DG-SGZ) of 9- and 12-month-old APPswe/PS1DeltaE9 tg mice was markedly reduced compared with age-matched nontransgenic littermates, whereas, the BMP4 mRNA level was significantly increased in the tg mice. There was a significant correlation between the increased BMP4 mRNA expression and the decreased number of BrdU labeled cells. After effectively blocking the expression of endogenous BMP4 with antisense oligodeoxynucleotides (ASODN), the decrease in hippocampal cell proliferation in the DG-SGZ and hilus of 9- and 12-month-old tg mice was reversed. These findings suggest that the increased expression of BMP4 mRNA within the DG of the hippocampus may contribute to the decrease in cell proliferation in APPswe/PS1DeltaE9 tg mice.     

Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities

Transgenic mice made by crossing animals expressing mutant amyloid precursor protein (APPswe) to mutant presenilin 1 (PS1dE9) allow for incremental increases in Abeta42 production and provide a model of Alzheimer-type amyloidosis. Here, we examine cognition in 6- and 18-month old transgenic mice expressing APPswe and PS1dE9, alone and in combination. Spatial reference memory was assessed in a standard Morris Water Maze task followed by assessment of episodic-like memory in Repeated Reversal and Radial Water maze tasks. We then used factor analysis to relate changes in performance in these tasks with cholinergic markers, somatostatin levels, and amyloid burden. At 6 months of age, APPswe/PS1dE9 double-transgenic mice showed visible plaque deposition; however, all genotypes, including double-transgenic mice, were indistinguishable from nontransgenic animals in all cognitive measures. In the 18-month-old cohorts, amyloid burdens were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). APPswe/PS1dE9 mice performed all cognitive tasks less well than mice from all other genotypes. Factor and correlation analyses defined the strongest correlation as between deficits in episodic-like memory tasks and total Abeta loads in the brain. Collectively, we find that, in the APPswe/PS1dE9 mouse model, some form of Abeta associated with amyloid deposition can disrupt cognitive circuits when the cholinergic and somatostatinergic systems remain relatively intact; and that episodic-like memory seems to be more sensitive to the toxic effects of Abeta.     

Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes

The basalo-cortical cholinergic system was characterized in mice expressing mutant human genes for presenilin-1 (PS1), amyloid precursor protein (APP), and combined PS/APP. Dual immunocytochemistry for ChAT and A beta revealed swollen cholinergic processes within cortical plaques in both APP and PS/APP brains by 12 months, suggesting aberrant sprouting or redistribution of cholinergic processes in response to amyloid deposition. At 8 months, cortical and subcortical ChAT activity was normal (PS/APP) or elevated (PS, APP frontal cortex), while cholinergic cell counts (nBM/SI) and receptor binding were unchanged. ChAT mRNA was up-regulated in the nBM/SI of all three transgenic lines at 8 months. The data indicate that the basal forebrain cholinergic system does not degenerate in mice expressing AD-related transgenes, even in mice with extreme amyloid load. The     

DHA diet reduces AD pathology in young APPswe/PS1ΔE9 transgenic mice: Possible gender effects

Epidemiological and clinical trial findings suggest that consumption of docosahexaenoic acid (DHA) lowers the risk of Alzhemier's disease (AD). We examined the effects of short‐term (3 months) DHA enriched diet on plaque deposition and synaptic deficts in forebrain of young APPswe/PS1ΔE9 transgenic (tg) and non‐transgenic (ntg) mice. Gas chromatography revealed a significant increase in DHA concomitant with a decrease of arachidonic acid in both brain and liver in mice fed with DHA. Female tg mice consumed relatively more food daily than ntg female mice, independent of diet. Plaque load was significantly reduced in the cortex, ventral hippocampus and striatum of female APPswe/PS1ΔE9 tg mice on DHA diet compared to female tg mice on control diet. Immunoblot quantitation of the APOE receptor, LR11, which is involved in APP trafficking and Aβ production, were unchanged in mice on DHA or control diets. Moreover drebrin levels were significantly increased in the hippocampus of tg mice on the DHA diet. Finally, in vitro DHA treatment prevented amyloid toxicity in cell cultures. Our findings support the concept that increased DHA consumption may play and important role in reducing brain insults in female AD patients. © 2009 Wiley‐Liss, Inc.     

Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice

OBJECTIVE: To demonstrate that in APPswe/PS1DeltaE9 transgenic mice, gene gun mediated Abeta42 gene vaccination elicits a high titer of anti-Abeta42 antibodies causal of a significant reduction of Abeta42 deposition in brain. METHODS: Gene gun immunization is conducted with transgenic mice using the Abeta42 gene in a bacterial plasmid with the pSP72-E3L-Abeta42 construct. Enzyme-linked immunoabsorbent assays (ELISA) and Western blots are used to monitor anti-Abeta42 antibody levels in serum and Abeta42 levels in brain tissues. Enzyme-linked immunospot (ELISPOT) assays are used for detection of peripheral blood T cells to release gamma-interferon. Immunofluorescence detection of Abeta42 plaques and quantification of amyloid burden of brain tissue were measured and sections were analyzed with Image J (NIH) software. RESULTS: Gene gun vaccination with the Abeta42 gene resulted in high titers of anti-Abeta42 antibody production of the Th2-type. Levels of Abeta42 in treated transgenic mouse brain were reduced by 60-77.5%. The Mann-Whitney U-test P=0.0286. INTERPRETATION: We have developed a gene gun mediated Abeta42 gene vaccination method that is efficient to break host Abeta42 tolerance without using adjuvant and induces a Th2 immune response. Abeta42 gene vaccination significantly reduces the Abeta42 burden of the brain in treated APPswe/PS1DeltaE9 transgenic mice with no overlap between treated and control mice.     

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.     

Fimbria-fornix lesion does not affect APP levels and amyloid deposition in the hippocampus of APP+PS1 double transgenic mice

The deposition of amyloid beta peptides (Abeta) and cholinergic dysfunction are two characteristic features of Alzheimer's disease. Several studies have suggested that a compromised cholinergic transmission can increase the amount of amyloid precursor protein (APP) in the denervated cortex (or hippocampus); however, whether this will increase Abeta production is unknown. To investigate the relation between cholinergic neurotransmission and APP metabolism, and the possible role of cholinergic dysfunction in the development of amyloid neuropathology, we lesioned the fimbria-fornix pathway in APP+PS1 double transgenic mice, at 5 and 7 months of age. Three months and 11 months postlesion, the mice were sacrificed for biochemical and histopathological analyses. The fimbria-fornix transection resulted in a substantial depletion of cholinergic markers in the hippocampus at both time points. Three months postlesion, hippocampal APP and Abeta levels were not significantly changed. At 11 months postlesion, the fimbria-fornix lesion did not result in an alteration in either the hippocampal Abeta levels or the extent of Abeta deposition, as assessed by amyloid plaque counts and image analysis of Abeta load in the 18-month-old APP+PS1 mice. Our findings indicate that APP metabolism in mice may be dissociated from cholinergic neurotransmission rather than related as previously suggested in other mammalian species.     

Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease

Transgenic mice carrying disease-linked forms of genes associated with Alzheimer disease often demonstrate deposition of the beta-amyloid as senile plaques and cerebral amyloid angiopathy. We have characterized the natural history of beta-amyloid deposition in APPswe/PS1dE9 mice, a particularly aggressive transgenic mouse model generated with mutant transgenes for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9). Ex vivo histochemistry showed Abeta deposition by 4 months with a progressive increase in plaque number up to 12 months and a similar increase of Abeta levels. In vivo multiphoton microscopy at weekly intervals showed increasing beta-amyloid deposition as CAA and plaques. Although first appearing at an early age, CAA progressed at a significantly slower rate than in the Tg2576 mice. The consistent and early onset of beta-amyloid accumulation in the APPswe/PS1dE9 model confirms its utility for studies of biochemical and pathological mechanisms underlying beta-amyloid deposition, as well as exploring new therapeutic treatments.     

Cortical cholinergic decline parallels the progression of Borna virus encephalitis.

Borna disease virus (BDV)-induced meningoencephalitis is associated with the dysfunction of the cholinergic system. Temporal development of this cholinergic decline during pre-encephalitic and encephalitic stages of BDV infection remains however elusive. Changes in choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were therefore determined in the cerebral cortex, hippocampus, striatum, amygdala and cholinergic basal forebrain nuclei (ChBFN) of rats infected with BDV. Immunocytochemistry for ChAT and vesicular acetylcholine transporter (VAChT) was employed to identify morphological consequences of BDV infection on cholinergic neurons. Whereas both ChAT and AChE activities changed only slightly under pre-encephalitic conditions, the encephalitic stage was characterized by a significant decrease of ChAT activity in the cerebral cortex, horizontal diagonal band of Broca (hDBB), hippocampus and amygdala concomitant with a marked reduction of AChE activity in the cerebral cortex, hDBB and hippocampus. The striatum and medial septum remained unaffected. ChAT and VAChT immunocytochemistry revealed prominent axonal degeneration in affected cortical and limbic projection areas of ChBFN. In summary, our data indicate progressive deterioration of forebrain cholinergic systems that parallels the progression of BDV encephalitis.     

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

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 (Aβ) 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 Aβ 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 Aβ plaque pathology.     

Longitudinal observation on CSF Abeta42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice

To relate levels of beta-amyloid42 (Abeta42) in the cerebrospinal fluid (CSF) and brain in early Alzheimer's disease, we repeatedly measured CSF Abeta42 levels in transgenic mice carrying Swedish amyloid precursor protein and presenilin-1 mutations, at ages before and after amyloid deposition. Hippocampal Abeta42 levels were measured at the endpoints. In APPswe/PS1(A246E) mice, CSF Abeta42 levels significantly increased between 5 and 7 months of age but did not change between 8 and 13 months despite a rapid increase in brain Abeta42. Furthermore, a decline in CSF Abeta42 levels was observed between 6 and 9 months in APPswe/PS1dE9 mice with faster pathology. Interestingly, the initial CSF Abeta42 concentrations correlated more strongly with brain Abeta42 levels than the endpoint CSF Abeta42. Our results suggest that the levels of CSF Abeta42 initially reflect the rate of Abeta42 production, but after reaching a critical concentration stay in equilibrium, until plaque formation leads to decreased CSF Abeta42 levels.     

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.     

Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1

Transgenic mice expressing both mutant amyloid precursor protein (APPswe) and presenilin-1 (PS1DeltaE9) develop amyloid deposits as early as 4 months of age and preliminary evidence suggests that this may be associated with degenerative changes in serotonin axons innervating the dentate gyrus of the hippocampus. In the present investigation, which focused on further delineating the effects of amyloid deposition on hippocampal neurochemistry, decreases in serotonin neurotransmitter levels (-25%) were discovered to be present at 18 months in APP+/PS1+ mice, while norepinephrine was reduced in the hippocampus of 12- (-30%) and 18-month-old (-45%) APP+/PS1+ double mutants. In addition, brain-derived neurotrophic factor (BDNF) protein levels were investigated since changes in BDNF are reported to occur in AD, and BDNF has been shown to have trophic effects on serotonin and norepinephrine neurons. In doubly, but not singly mutant mice, hippocampal BDNF levels were increased at 12 (+70%) and 18 months (+170%). Furthermore, in a different model of serotonergic and noradrenergic degeneration, BDNF protein levels were similarly increased in response to depletions in hippocampal serotonin and norepinephrine caused by the chemical neurotoxin 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP). These findings show that early amyloid deposition in mice expressing mutant human APP and PS-1 is associated with a progressive loss of serotonin and norepinephrine neurotransmitter levels in the hippocampus later in life. Furthermore, BDNF protein levels are increased in APP+/PS1+ and 2'-NH2-MPTP-treated mice, possibly as a compensatory response to serotonergic and noradrenergic neurodegeneration in a brain region important for learning and memory.     

Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1-42).

The main objective of the present study was to develop an alternative singly-transgenic (tg) hAPP model where amyloid deposition will occur at an earlier age. For this purpose, we generated lines of tg mice expressing hAPP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine (m)Thy-1 gene (mThy1-hAPP751). In the brains of the highest (line 41) and intermediate (lines 16 and 11) expressers, high levels of hAPP expression were found in neurons in layers 4-5 of the neocortex, hippocampal CA1 and olfactory bulb. As early as 3-4 months of age, line 41 mice developed mature plaques in the frontal cortex, whereas at 5-7 months plaque formation extended to the hippocampus, thalamus and olfactory region. Ultrastructural and double-immunolabeling analysis confirmed that most plaques were mature and contained dystrophic neurites immunoreactive with antibodies against APP, synaptophysin, neurofilament and tau. In addition, a decrease in the number of synaptophysin-immunoreactive terminals was most prominent in the frontal cortex of mice from line 41. Mice from line 11 developed diffuse amyloid deposits at 11 months of age, whereas mice from line 16 did not show evidence of amyloid deposition. Analysis of Abeta by ELISA showed that levels of Abeta(1-40) were higher in mice that did not show any amyloid deposits (line 16), whereas Abeta(1-42) was the predominant species in tg animals from the lines showing plaque formation (lines 41 and 11). Taken together this study indicates that early onset plaque formation depends on levels of Abeta(1-42).     

Decreased proliferation of hippocampal progenitor cells in APPswe/PS1dE9 transgenic mice

A recent hypothesis suggests that there is impaired hippocampal neurogenesis in Alzheimer's disease. Here we examined the proliferation, the first stage in neurogenesis, of hippocampal progenitor cells in amyloid precursor protein with Swedish mutation and presenilin-1 with deletion of exon 9 (APPswe/PS1dE9) transgenic mice. Compared with age-matched wild-type mice, transgenic mice at 5 months of age with low amyloid beta-peptide (Abeta) levels and subtle Abeta deposits showed normal proliferation of hippocampal progenitor cells; however, transgenic mice at 9 months of age with high Abeta levels and numerous Abeta deposits showed decreased proliferation of these cells. The number of proliferating cells in male transgenic mice was indistinguishable from that in female transgenic mice. These results indicate that neurogenesis is decreased with degrees of Abeta pathology, and that there is no gender difference in their proliferation in APPswe/PS1dE9 transgenic mice.     

Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT

Activity of choline acetylase (ChAT) was measured in basal forebrain cholinergic nuclei and in projection sites of these cells in the hippocampus and cortex of young rats and of aged rats who showed impaired performance on the radial arm maze. Decreased ChAT activity was found in the vertical diagonal band nucleus, the dentate gyrus and striatum of aged rats.     

The beta-amyloid-related proteins presenilin 1 and BACE1 are axonally transported to nerve terminals in the brain

In this study, we show that removal of entorhinal cortex (ERC) afferents to hippocampus reduces levels of presenilin 1 (PS1) in the dentate gyrus of APPswe/PS1DeltaE9 transgenic (Tg) mice. PS1 immunoreactivity on the deafferented dentate gyrus decreases by approximately 25% and 50%, 2 and 4 weeks post-lesion compared to the contralateral side; by Western blotting, there is an approximately 40% decrease of the 43 kDa (full length) PS1 and an approximately 80% decrease of the 28 kDa (N-terminal fragment) PS1 on the lesioned dentate gyrus. Levels of beta-site APP Cleavage Enzyme 1 (BACE1) immunoreactivity also decrease by approximately 50% and 65% 2 and 4 weeks post-lesion. Together, these data demonstrate that PS1 and BACE1 are transported from the entorhinal cortex to the hippocampus via axons of the perforant pathway.     

Galanin plasticity in the cholinergic basal forebrain in Alzheimer's disease and transgenic mice

Galanin (GAL) is a biologically active 29 amino acid (30 in humans) which participates in the modulation of several ascending neurotransmitter systems including cholinergic basal forebrain (CBF) neurons, which undergo extensive degeneration in Alzheimer's disease (AD). GAL immunoreactive fibers within the CBF display hypertrophy and hyperinnervate surviving CBF neurons in late AD. Over the years, this unique neuronal plasticity response has been an active area of research for our group. We have examined tissue from a clinically well characterized cohort of retired elderly clergy to determine whether people with mild cognitive impairment display GAL hyperinnervation upon CBF neurons. We found that GAL hyperinnervation is a late stage event and that CBF neuron reduction is not correlated with GAL over expression during prodromal AD. Interestingly, findings from our laboratory using tau immunohistochemistry and single cell gene array technologies suggest that GAL remodeling may influence neurofibrillary tangle formation by altering tau phosphorylation events in CBF neurons in AD. Studies using GAL-tg mice suggest that GAL over expression reduces the cholinergic phenotype but does not produce a frank loss of CBF cells. This phenotypic down regulation of ChAT is reminiscent of the lack of a frank CBF neuron loss in prodromal AD. Moreover, studies using mice transgenic for both the amyloid precursor protein (APP) and presenilin-1 (PS1) bearing AD-related mutations (APPswe/PS1delta9) displayed increased GAL immunoreactive fibers, neurities and plaques in cortex and hippocampus. These fin'dings provide evidence for a mechanistic relationship between amyloidosis and GAL over expression in AD. Understanding GALs role in the clinical and pathological features of AD, may lead to novel drug treatments for this disease.     

Selective persistent reduction in choline acetyltransferase activity in basal forebrain of the rat after thyroid deficiency during early life

The effect of thyroid deficiency on the activity of choline acetyltransferase (ChAT; the marker for cholinergic neurons) was studied in different parts of the rat brain at ages 5, 10, 15 and 25 days, and at day 130 following 102 days of rehabilitation. During normal development, the activity of ChAT increased in the cerebral cortex, hippocampus and basal forebrain, and decreased in the cerebellum. Neonatal thyroid deficiency resulted in a marked retardation of the developmental patterns of the enzyme activity. In the hippocampus the effect diminished with age even during the period of thyroid hormone deprivation, while in the cerebral cortex and cerebellum the enzyme activity was restored to normal only after rehabilitation. In contrast, ChAT activity in the basal forebrain remained persistently reduced in comparison with controls. The results indicate that neonatal thyroid deficiency causes selective irreversible biological damage to subcortical cholinergic neurons.     

Long-term effects of basal forebrain lesions on cholinergic, noradrenergic and serotonergic markers in mouse neocortex

Lesions of basal forebrain cholinergic neurons projecting to cerebral cortex and hippocampus have recently been exploited as animal models for some of the neurochemical and behavioral deficits of Alzheimer's disease. We have observed that electrolytic lesions of cholinergic basal forebrain nuclei can lead to morphological plasticity in adult mouse cortex. In the present study, the acute and chronic sequelae of basal forebrain electrolytic lesion on cortical synaptic chemistry have been examined. In addition to choline acetyltransferase (ChAT) activity, levels of norepinephrine and of serotonin were reduced within a week after the lesion. Recovery of ChAT activity and of serotonin levels began within a month after the lesion. Serotonin type 2 receptor binding exhibited an acute reduction after the lesion in ipsilateral cortex, followed later by a chronic bilateral decrease. No significant changes in beta-adrenergic receptors were apparent at any time after the lesion despite a permanent and bilateral reduction of norepinephrine levels after the lesion. The potential significance of these results for cortical plasticity regulation and Alzheimer's disease is discussed.