Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls

Polyclonal antibodies to synthetic peptides homologous to amino acid residues 45-62, 597-624, and 676-695 of the predicted sequence of Alzheimer's amyloid precursor protein (APP) were used to investigate the site of origin of APP, and the relationship between APP and amyloid protein in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Cortical sections as well as homogenates of isolated leptomeningeal and cortical microvessels from three patients with AD, two patients with HCHWA-D, and two nondemented controls were probed. In vessel extracts of both groups of patients and the controls, APP was detected as a set of proteins with electrophoretic mobility of 105 to 135 kilodaltons. In cortical sections of all subjects, APP immunoreactivity was found in leptomeningeal and cortical vessel walls. In patients with AD and HCHWA-D, APP and amyloid fibrils coexisted in the same vessels. Moreover, APP immunoreactivity was found in association with 50% of senile plaques in AD brains, but was not evidenced in parenchymal amyloid deposits in patients with HCHWA-D. These data suggest that the vascular system is a source of APP and that the processing of APP into insoluble fibrils in AD and HCHWA-D may take place in situ.     

Accumulation of amyloid-beta protein in exocrine glands of transgenic mice overexpressing a carboxyl terminal portion of amyloid protein precursor

Amyloid-beta protein (Abeta) and its precursor (betaPP) play important roles in the pathogenesis of Alzheimer disease and inclusion-body myositis. In humans, Abeta deposits are found in brain, skeletal muscle, and skin. Therefore, we have investigated possible Abeta deposits in multiple tissues of two transgenic mouse lines overexpressing the signal plus Abeta-bearing 99-amino acid carboxyl terminal sequences of betaPP under the control of a cytomegalovirus enhancer/beta-actin promoter. One of the lines developed Abeta-immunoreactive intracellular deposits consistently in the pancreas and lacrimal gland, and occasionally in gastric, DeSteno's, and lingual glands. Although the Abeta deposits increased during ageing and degenerative changes of the tissues were observed, little or no extracellular Abeta deposits were observed up to the age of 25 months. These lines of transgenic mice are useful for studying the molecular mechanisms of development and clearance of intracellular Abeta deposits.     

淀粉样蛋白前体/早老素1转基因小鼠大脑皮质内kinesin1介导的神经元轴浆运输障碍

目的 探讨轴突运输蛋白,kinesin1和神经丝蛋白（SIM-312）在阿尔茨海默病(AD)发生、发展中的作用。 方法 出生后30～360 d淀粉样蛋白前体（APP）/早老素1（PS1）转基因小鼠（n＝40）和野生型小鼠（n＝40）用于此研究,利用免疫荧光染色和Western blotting技术检测上述两种小鼠大脑皮层内老年斑的沉积及星形胶质细胞的分布以及在大脑皮质发育过程中kinesin1和SIM-312阳性细胞个数及蛋白的表达变化。 结果 APP/PS1转基因小鼠与正常对照组相比,β-淀粉样蛋白（Aβ）斑块增多,星形胶质细胞数目增多,神经元减少;而kinesin1阳性细胞的数量在APP/PS1转基因小鼠生长发育过程中减少,且在出生9月（P9M）之后与野生型小鼠之间差异存在着显著性 (P<0.05);SIM-312标记的神经丝蛋白随着年龄的增长自P6M之后开始出现缠结现象。 结论 Kinesin1和SIM-312的异常改变导致神经元中轴浆运输障碍以及AD的病理变化。     

Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment

Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (Abeta) peptides and to enhance Abeta toxicity. Tg2576 (transgenic mice carrying the Swedish mutation of amyloid precursor protein, APPswe) mice and mice overexpressing human synaptic acetylcholinesterase (AChE-S) were crossed (hAChE-Tg//APPswe), to study the effects of brain Abeta, from 1 to 10 months of age, under the constant influence of AChE-S. The effect of nicotine treatment was also evaluated in these mice since we have previously shown that nicotine dramatically decreases Abeta levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg// APPswe mice showed increased levels of cortical insoluble Abeta1-40 and Abeta1-42 compared with APPswe mice, whereas APPswe mice displayed increased soluble Abeta1-40. Abeta plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [125I]alpha-bungarotoxin binding sites or hippocampal glial fibrillary acidic protein (GFAP) immunoreactivity between hAChE-Tg//APPswe, and APPswe mice at either 1 or 10 months of age. L(-)-Nicotine (final dose 0.45 mg/kg) treatment twice daily for 10 days to 14-month-old hAChE-Tg// APPswe mice increased cortical insoluble Abeta1-40 levels, while both L(-)- and D(+)-nicotine (final dose 0.45 mg/kg) increased soluble Abeta1-42. L(-)-Nicotine reduced hippocampal GFAP immunoreactivity both in hAChE-Tg//APPswe mice and non-transgenic controls, while D(+)-nicotine caused a decrease only in hAChE-Tg//APPswe mice. Moreover, D(+)-nicotine increased the [125I]alpha-bungarotoxin binding sites in the hippocampus, and cortex of the hAChE-Tg//APPswe mice. In conclusion, already at a very young age, hAChE-Tg// APPswe mice exhibit increased levels of aggregated Abeta compared with APPswe mice, due to the possible interaction between Abeta and AChE-S, whereas APPswe mice exhibit increased soluble Abeta. The interaction between Abeta and AChE-S may also explain the different effect of nicotine on Abeta pathology in the hAChE-Tg//APPswe mice. The results in this study emphasize the importance of using different transgenic mouse models for evaluating the effect of new drug candidates for the treatment of Alzheimer's disease.     

Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss

To analyze the relationship between the deposition of amyloid beta peptides (Abeta) and neuronal loss in transgenic models of Alzheimer's disease (AD), we examined the frontal neocortex (Fc) and CA1 portion of hippocampus (CA1) in PSAPP mice doubly expressing AD-associated mutant presenilin 1 (PS1) and Swedish-type mutant beta amyloid precursor protein (APPsw) by morphometry of Abeta burden and neuronal counts. Deposition of Abeta was detected as early as 3 months of age in the Fc and CA1 of PSAPP mice and progressed to cover 28.3% of the superior frontal cortex and 18.4% of CA1 at 12 months: approximately 20- (Fc) and approximately 40- (CA1) fold greater deposition than in APPsw mice. There was no significant difference in neuronal counts in either CA1 or the frontal cortex between nontransgenic (non-tg), PS1 transgenic, APPsw, and PSAPP mice at 3 to 12 months of age. In the PSAPP mice, there was disorganization of the neuronal architecture by compact amyloid plaques, and the average number of neurons was 8 to 10% fewer than the other groups (NS, P > 0.10) in CA1 and 2 to 20% fewer in frontal cortex (NS, P = 0.31). There was no loss of total synaptophysin immunoreactivity in the Fc or dentate gyrus molecular layer of the 12-month-old PSAPP mice. Thus, although co-expression of mutant PS1 with Swedish mutant betaAPP leads to marked cortical and limbic Abeta deposition in an age-dependent manner, it does not result in the dramatic neuronal loss in hippocampus and association cortex characteristic of AD.     

Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice

Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, central cholinergic dysfunction, and dementia; however, the relationship between these parameters is not well understood. We studied the effect of amyloid peptide formation and deposition on central cholinergic function in knock-in mice carrying the human amyloid precursor protein (APP) gene with the Swedish/London double mutation (APP-SL mice) which were crossbred with transgenic mice overexpressing normal (PS1wt) or mutated (M146L; PS1mut) human presenilin-1. APP-SLxPS1mut mice had increased levels of Abeta peptides at 10 months of age and amyloid plaques at 14 months of age while APP-SLxPS1wt mice did not have increased peptide levels and did not develop amyloid plaques. We used microdialysis in 15-27 months old mice to compare hippocampal acetylcholine (ACh) levels in the two mouse lines and found that extracellular ACh levels were slightly but significantly reduced in the APP-SLxPS1mut mice (-26%; P=0.044). Exploratory activity in the open field increased hippocampal ACh release by two-fold in both mouse lines; total and relative increases were not significantly different for the two strains under study. Similarly, infusion of scopolamine (1 microM) increased hippocampal ACh release to a similar extent (3-5-fold) in both groups. High-affinity choline uptake, a measure of the ACh turnover rate, was identical in both mouse lines. Neurons expressing choline acetyltransferase were increased in the septum of APP-SLxPS1mut mice (+26%; P=0.046). We conclude that amyloid peptide production causes a small decrease of extracellular ACh levels. The deposition of amyloid plaques, however, does not impair stimulated ACh release and proceeds without major changes of central cholinergic function.     

Cleavage of amyloid precursor protein elicited by chronic cerebral hypoperfusion

In the present study, we sought to determine whether low-grade, chronic vascular insufficiency induced in a rodent model of chronic cerebrohypoperfusion is sufficient, in and of itself, to trigger cleavage of the amyloid precursor protein (APP) into beta A-sized fragments. We report that chronic two vessel occlusion (2VO) results in progressive accumulation of beta A peptides detected by Western analysis in aged rats correlating with a shift in the immunohistochemical localization of APP from neurons to extracellular deposits in brain parenchyma. These data indicate that the 2VO paradigm reproduces features of beta A biogenesis characteristic of sporadic Alzheimer's disease.     

Seizure susceptibility and mortality in mice that over-express amyloid precursor protein

Alzheimer's disease and Fragile X syndrome both display synaptic phenotypes, and based on recent studies, likely share dendritic over expression of amyloid precursor protein (APP) and beta-amyloid (Abeta). In order to create a mouse model to specifically study the effects of APP and Abeta at synapses, we crossed Tg2576, which over-express human APP with the Swedish mutation (hAPPsw), with fmr-1 KO mice. The progeny, named FRAXAD, displayed increased mortality (23% by 30 days of age) compared to Tg2576 (3%) and WT and fmr-1 KO littermate controls (0%) consistent with a developmental defect. By 60 days of age, both the Tg2576 and FRAXAD mice approached a 40% mortality rate compared to 0% for WT and fmr-1 KO littermates. To understand the mechanism underlying increased mortality in APP over-expressing mice, we assessed seizure thresholds in response to pentylenetetrazol (PTZ). Both the Tg2576 and FRAXAD mice had a lower threshold to PTZ-induced seizures (average seizure score of >/=4.0) in comparison to nontransgenic littermates (average seizure score 1.9-2.9). Seizures are a major phenotype of AD, FXS, Down syndrome, autism and epilepsy, and these data suggested that developmental over-expression of dendritic APP or Abeta increased seizure susceptibility.     

Altered auditory-evoked potentials in mice carrying mutated human amyloid precursor protein and presenilin-1 transgenes

Transgenic mice carrying human APPswe and PS1-A264E transgenes (A/P mice) have elevated levels of the highly fibrillogenic amyloid Abeta(1-42) (Abeta) and develop amyloid plaques around the age of 9 months. Our aim was to find whether the gradual accumulation of Abeta in these mice can be detected with long-term recording of auditory-evoked potentials. The A/P double-mutant mice had impaired auditory gating and a tendency toward increased latency of the cortical N35 response, but these changes were not age-dependent between 7 and 11 months of age. In a control experiment that included also APP and PS1 single-mutant mice, the A/P double-mutant mice had weaker auditory gating than either APP or PS1 mice. In contrast, increased N35 latency was found in both A/P and APP mice compared with nontransgenic or PS1 mice. The Abeta40 and Abeta42 levels were robustly increased in A/P mice and Abeta40 moderately increased also in APP mice. Plaques were deposited only in A/P mice. We conclude that the impaired auditory gating is associated with the overproduction Abeta42 but does not reflect its amount. In contrast, increased N35 latency is related to the APP genotype independent of Abeta42 production.     

Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein

PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimer's disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.     

Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.     

敲除淀粉样前体蛋白基因促进铝诱导的小鼠认知障碍损伤

目的 淀粉样前体蛋白(APP)基因是与痴呆症发生发展相关的重要基因,利用APP基因敲除小鼠探讨铝诱导的认知障碍损伤,及APP对中
毒性认知障碍损伤的作用。方法 3月龄同窝阴性小鼠分为野生对照组（WT）和铝处理组（WT+Al）,APP敲除小鼠分为模型对照组（APP^-/- ）和
模型处理组（APP^-/- +Al）,每组10只。铝处理组在粮食中加入相应剂量的乳酸铝,同窝阴性小鼠和APP^-/-小鼠给予常规鼠粮作为对照,乳酸
铝处理8周后进行水迷宫实验。HE染色观察小鼠脑组织神经病理改变;Western blotting检测糖原合成激酶3β(GSK-3β)和Caspase-3的活性变
化。结果 与WT相比,WT+Al小鼠在原平台区域停留时间和穿越原平台区域次数减少了28.1%和18.8%,而APP^-/- +Al小鼠在原平台区域停留时间
和穿越原平台区域次数减少了44.1%和51%。Western blotting显示,WT+Al小鼠和APP^-/-+Al小鼠脑组织中p-GSK-3β分别减少了17.4%和46.4%。结论 APP基因敲除促进铝诱导的神经毒性和学习记忆损伤。APP基因敲除导致GSK-3β的磷酸化水平降低、活性增高。由于GSK-3β活性增加对痴呆症具有促进作用,推测APP通过抑制GSK-3β活性在痴呆症发生过程中发挥保护效应。     

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.     

Ganglioside GM1 binding the N-terminus of amyloid precursor protein

Secreted amyloid precursor protein (APPs) plays a role in several neuronal functions, including the promotion of synaptogenesis, neurite outgrowth and neuroprotection. Previous study has demonstrated that ganglioside GM1 inhibits the secretion of APPs; however the underlying mechanism remains unknown. Here we reported that GM1 can bind cellular full length APP and APPs secreted from APP(695) stably-transfected SH-SY5Y cells. To characterize the GM1-APP interaction further, we expressed and purified recombinant fragments of the N-terminal APP. Immunoprecipitation experiments revealed that GM1 was able to bind the recombinant APP(18-81) fragment. Moreover, the synthetic peptide APP(52-81) could inhibit the binding. Therefore, the binding site for GM1 appears to be located within residues 52-81 of APP. Furthermore, we found that only GM1, but not GD1a, GT1b and ceramide, binds APP-N-terminus, indicating that the specific binding depends on the sugar moiety of GM1. Fluorescent studies revealed a decrease in the intrinsic fluorescence intensity of the APP(52-81) peptide in phosphatidylcholine (PC)/GM1 vesicles. By using FTIR techniques, we found that the major secondary structure of the APP(52-81) peptide was altered in PC/GM1 vesicles. Our results demonstrate that GM1 binds the N-terminus of APP and induces a conformational change. These findings suggest that secreted APP is decreased by membrane GM1 binding to its precursor protein and provide a possible molecular mechanism to explain the involvement of GM1 in APP proteolysis and pathogenesis of Alzheimer's disease.     

Caspase-cleaved amyloid precursor protein in Alzheimer's disease

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.     

Bosentan preserves endothelial function in mice overexpressing APP

This study was designed to test the hypothesis that Alzheimer's disease (AD) is associated with endothelial dysfunction and that chronic endothelin-1 antagonism preserves endothelial function in mice overexpressing the AD amyloid precursor protein (APP). Three groups of mice were studied: C57BL/6 (normal control, n = 6), transgenic mice overexpressing APP (Tg2576, n = 5), and Tg2576 mice fed Bosentan (100 mg/(kg day)(-1)), a combined endothelin A and B receptor antagonist, for 4 months (Tg2576+Bosentan, n = 5). Mice were sacrificed at the age of 7 months. In vitro, the endothelium-dependent aortic vasorelaxation was significantly attenuated in Tg2576 mice as compared to C57BL/6 and Tg2576+Bosentan mice. In contrast, Tg2576+Bosentan and C57BL/6 mice showed similar endothelium-dependent aortic vasorelaxation. Similarly, endothelium-dependent carotid vasorelaxation was significantly attenuated in Tg2576 mice compared to C57BL/6 and Tg2576+Bosentan mice. There was no difference between the three groups in the response to nitroprusside. The current study demonstrates the presence of endothelial dysfunction in both carotid and aortic arteries in mice overexpressing APP and suggests a pathophysiological role for the endogenous endothelin system in AD.     

Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice

Proteases and their inhibitors play key roles in physiological and pathological processes. Cerebral amyloid plaques are a pathological hallmark of Alzheimer's disease (AD). They contain amyloid-ss (Ass) peptides in tight association with the serine protease inhibitor alpha(1)-antichymotrypsin.(1,2) However, it is unknown whether the increased expression of alpha(1)-antichymotrypsin found in AD brains counteracts or contributes to the disease. We used regulatory sequences of the glial fibrillary acidic protein gene(3) to express human alpha(1)-antichymotrypsin (hACT) in astrocytes of transgenic mice. These mice were crossed with transgenic mice that produce human amyloid protein precursors (hAPP) and Ass in neurons.(4,5) No amyloid plaques were found in transgenic mice expressing hACT alone, whereas hAPP transgenic mice and hAPP/hACT doubly transgenic mice developed typical AD-like amyloid plaques in the hippocampus and neocortex around 6 to 8 months of age. Co-expression of hAPP and hACT significantly increased the plaque burden at 7 to 8, 14, and 20 months. Both hAPP and hAPP/hACT mice showed significant decreases in synaptophysin-immunoreactive presynaptic terminals in the dentate gyrus, compared with nontransgenic littermates. Our results demonstrate that hACT acts as an amyloidogenic co-factor in vivo and suggest that the role of hACT in AD is pathogenic.     

Retinal dysfunction and progressive retinal cell death in SOD1-deficient mice

The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase (SOD1) in mice leads to many different phenotypes that resemble accelerated aging. The purpose of this study was to examine the morphology and physiology of the sensory retina in Sod1(-/-) mice. The amplitudes of the a- and b-waves of electroretinograms elicited by stimuli of different intensity were reduced in senescent Sod1(-/-) mice, and this reduction in amplitude was more pronounced with increasing age. Retinal morphometric analyses showed a reduced number of nuclei in both the inner nuclear cell layer and outer nuclear cell layer. Electron microscopy revealed swollen cells and degenerated mitochondria in the inner nuclear cell and outer nuclear cell layer of senescent Sod1(-/-) mice indicating necrotic cell death. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling revealed no significant differences in the number of apoptotic cells between Sod1(-/-) and wild-type mice, and activated caspase-3 could not be detected in the retina of Sod1(-/-) mice. In addition to the age-related macular degeneration-like phenotypes previously reported, Sod1(-/-) mice also present progressive retinal degeneration. Our results indicate that Sod1(-/-) mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated retinal degeneration.     

Diffuse amyloid deposition,but not plaque number,is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidbeta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Abeta and the deposition of Abeta in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 months post-lesion. Diffuse amyloid deposits in the deafferented terminal fields of area CA1 and subiculum were dramatically reduced as assessed by image analysis of the Abeta load. Our findings indicate that neuronal ablations decrease diffuse amyloid deposits in the terminal fields of these neurons, and, further, that pathway lesions similarly decrease the amount of diffuse amyloid deposits in the terminal fields of the lesioned axons. Together, this suggests that the axonal transport of APP and/or Abeta and subsequent secretion of Abeta at terminals plays an important role in the deposition of Abeta protein in Alzheimer's disease, and, further, that diffuse deposits do not develop into plaques.py>