LRP and senile plaques in Alzheimer's disease: colocalization with apolipoprotein E and with activated astrocytes

The low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which is present on senile plaques in Alzheimer's disease (AD). It is suggested to play an important role in the balance between amyloid beta (Abeta) synthesis and clearance mechanisms. One of its ligands, apolipoprotein E (apoE), is also present on senile plaques and has been implicated as a risk factor for AD, potentially affecting the deposition, fibrillogenesis and clearance of Abeta. Using immunohistochemistry we show that LRP was present only on cored, apoE-containing senile plaques, in both PDAPP transgenic mice and human AD brains. We detected strong LRP staining in neurons and in reactive astrocytes, and immunostaining of membrane-bound LRP showed colocalization with fine astrocytic processes surrounding senile plaques. LRP was not present in plaques in young transgenic mice or in plaques of APOE-knockout mice. As LRP ligands associated with Abeta deposits in AD brain may play an important role in inducing levels of LRP in both neurons and astrocytes, our findings support the idea that apoE might be involved in upregulation of LRP (present in fine astrocytic processes) and act as a local scaffolding protein for LRP and Abeta. The upregulation of LRP would allow increased clearance of LRP ligands as well as clearance of Abeta/ApoE complexes.     

Coexistence of Creutzfeldt‐Jakob disease,Lewy body disease,and Alzheimer's disease pathology: An autopsy case showing typical clinical features of Creutzfeldt‐Jakob disease

We report here an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) without hereditary burden and with a clinical course typical of sporadic CJD. A 77‐year old man developed memory disturbance, followed by gait disturbance and myoclonus. He died of bronchopneumonia 5 months after the disease onset. Post‐mortem examination revealed neuronal loss, astrocytosis, and patchy spongiosis in the cerebral cortex and lenticular nuclei. Synaptic‐type deposits of prion protein were present in the cerebral cortex. Additionally, Lewy bodies were observed in the cerebral cortex and substantia nigra. Furthermore, senile plaques compatible with definite Alzheimer's disease according to Consortium to Establish a Registry for Alzheimer's disease criteria and neurofibrillary changes of the limbic system consistent with Braak stage IV were found. Based on a review of the published literature, this autopsy case is very rare, and we suppose that the incidence of CJD accompanied by Lewy body disease and Alzheimer's disease is very low.     

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer’s disease

Current evidence shows that apolipoprotein E(APOE), apolipoprotein CI(APOC1) and low density lipoprotein receptor-related protein(LRP) variations are related to late-onset Alzheimer's disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer's disease patients. We performed a 30-month longitudinal cohort study to investigate the relationship between Alzheimer's disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer's disease were recruited form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess patients' cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE ε4 carriers compared with non-carriers. In addition, the APOE ε4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive impairment progression group. In conclusion, APOE ε4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ε4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer's disease.     

Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease

To assess the relationship between dementia, neuronal loss, and neuropathological findings in Alzheimer's disease (AD), we counted the number of neurons, senile plaques, and neurofibrillary tangles in a high-order association cortex. We studied the superior temporal sulcus of 34 individuals with AD and 17 nondemented control subjects, using statistically unbiased, stereological counting techniques. The number of superior temporal sulcus neurons in nondemented control subjects was stable across the sixth to ninth decades. In AD, more than 50% of the neurons were lost. Both neuronal loss and neurofibrillary tangles increased in parallel with the duration and severity of illness, but the amount of neuronal loss exceeded by manyfold the amount of neurofibrillary tangles accumulated. In contrast to the correlation between neurofibrillary tangels and neuronal loss, the number of senile plaques and the percentage of the superior temporal sulcus that was covered by Aβ (amyloid burden) were not related to neuronal loss, number of neurofibrillary tangles, or duration of disease. Neither the amount nor the rate of neuronal loss in the superior temporal sulcus in AD correlated with apolipoprotein E genotype. These data suggest that neuronal loss in association areas such as the superior temporal sulcus contributes directly to cognitive impairment in AD.     

A subset of senile dementia with high incidence of the apolipoprotein E ϵ2 allele

There is a subset of very elderly patients with senile dementia in whom abundant neurofibrillary tangles are present, mainly in the hippocampal region, without a significant number of senile plaques. In a retrospective neuropathological examination of 239 dementia patients, 14 were found to have this type of senile dementia. The apolipoprotein E ?2, ?3, and ?4 allele frequencies in this patient group were 0.39, 0.50, and 0.11, respectively. Such a high frequency of the ?2 allele suggests that this type of dementia is distinct from Alzheimer's disease not only from a neuropathological but also from a genetic viewpoint.     

Verteilungsmuster der senilen Veränderungen in den Hirnstammkernen

A quantitative study of senile plaques and Alzheimer's fibrillary changes in nuclei of the brain stem and hypothalamic regions in senile dementia and Alzheimer's disease demonstrated these particular changes to be far less marked than those observed in the cortex. In seven cases each of senile dementia and Alzheimer's disease, the numbers of senile plaques and undergoing Alzheimer's fibrillary changes were determined and compared between the cortex and 17 nuclei in the brain stem and hypothalamic regions. In all cases, four cortical regions were noted to have undergone severe changes, while some of nuclei of the brain stem showed Alzheimer's fibrillary changes. Senile plaques were very few in the brain stem; the substantia innominata, nucleus centralis raphe and corpus mammillare were found to exhibit a slight degree of this pathological change in five cases only. Even in those nuclei of the brain stem which were relatively abundant in Alzheimer's fibrillary changes, the number of areas undergoing such changes was no more than one-tenth of that of the cortex. Most abundant in Alzheimer's fibrillary changes were the nucleus centralis superior and nucleus dorsalis raphe, followed by the nucleus rnagnocellularis, formatio reticularis, nucleus caeruleus and nucleus alae cinereae. These changes, though of a slightest degree, were also observed in the substantia innominata, substantia griesea cntralis mesence-phali and nucleus originis nervi cochlearis ventralis. Worthy of a paticular note is that nuclei which were most severely affected with these senile changes are those having mono-amines.     

LRP and Alzheimer's disease

The low-density lipoprotein receptor (LDLR)-related protein, LRP, is a unique member of the LDLR family. Frequently referred to as a scavenger receptor, LRP is a large transmembrane endocytic receptor that can bind and internalize many functionally distinct ligands. Besides its role as a cargo-receptor, LRP has also been implicated in many signaling pathways. LRP knockout mice die at early embryonic age, which strongly suggests that LRP's functions are essential for normal development. Within the CNS, LRP is highly expressed in neuronal cell bodies and dendritic processes. In vitro, neurite outgrowth is stimulated by apolipoprotein E (apoE)-containing lipoprotein particles via binding to LRP. ApoE is the major cholesterol transporter in the brain and human carriers of one or two copies of the e4 allele of apoE are at a higher risk of developing Alzheimer's disease (AD). LRP also binds the amyloid precursor protein (APP) and its proteolytic fragment, the amyloid-beta peptide (Abeta), which are major players in the pathogenesis of AD. Finally, LRP has been linked to AD by genetic evidence. In this review we discuss the potential mechanisms by which LRP can affect APP and Abeta metabolism, and therefore contribute to the pathogenesis of AD.     

The molecular significance of amyloid β-peptide for Alzheimer's disease

Alzheimer's disease is the most common form of dementia. Although the majority of the cases occur sporadically, in some rare cases Alzheimer's disease is genetically inherited. Pathologically, Alzheimer's disease is characterized by the accumulation of senile plaques within the extracellular space of brain regions known to be important for intellectual functions. In addition to senile plaques, deposits of identical biochemical composition are found in the walls of meningeal and cerebral blood vessels. Senile plaques are surrounded by degenerating neurons indicating a toxic interference of amyloid plaques with neurons. The major component of senile plaques is the 4 kDa amyloid β-peptide. This peptide has been shown to exhibit neurotoxic properties when added to cultured neurons, or injected into rat brains. Amyloid β-peptide is derived from a high molecular weight precursor, the β-amyloid precursor protein, by proteolytic processing. Mutations responsible for the early onset of Alzheimer's disease in some families are found within the gene coding for the β-amyloid precursor protein. These mutations strongly influence the generation of amyloid β-peptide resulting in a significant overproduction of the peptide or the generation of elongated forms which are known to aggregate and precipitate much faster. Moreover, mutations found in other genes known to cause early onset of Alzheimer's disease have been shown to interfere directly with the production or precipitation of amyloid β-peptide.     

Electron-Microscopical Study on Senile Plaques in Alzheimer's Disease

The cerebral cortex taken post mortem from a case of Alzheimer's disease was examined especially with regard to the relation between blood vessels and senile plaques. Many senile plaques had central cores, composed of such matter as degenerated blood vessels and basement membranes with abundant amyloid fibrils. The components of senile plaques seemed to be degenerated neuronal and glial tissue compressed by developed basement membranes and amyloid fibrils. From this we would like to emphasize that senile plaques seem to be caused by amyloid fibrils and degenerated capillaries.     

Expression of alpha(2)-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) in rat microglial cells

Low density lipoprotein receptor-related protein (LRP) participates in the uptake and degradation of several ligands implicated in neuronal pathophysiology including apolipoprotein E (apoE), activated alpha(2) -macroglobulin (alpha(2)M*) and beta-amyloid precursor protein (APP). The receptor is expressed in a variety of tissues. In the brain LRP is present in pyramidal-type neurons in cortical and hippocampal regions and in astrocytes that are activated as a result of injury or neoplasmic transformation. As LRP is expressed in the monocyte/macrophage cell system, we were interested in examining whether LRP is expressed in microglia. We isolated glial cells from the brain of neonatal rats and LRP was immunodetected both in microglial cells and in astrocytes expressing glial fibrillar acidic protein (GFAP). Microglial cells were able to bind and internalize LRP-specific ligand, alpha(2)M*. The internalization was inhibitable by RAP, with a Kd of 1.7 nM. The expression of LRP was up-regulated by dexamethasone, and down-regulated by lipopolysaccharide (LPS), gamma interferon (IFN-gamma) or a combination of both. LRP was less sensitive to dexamethasone in activated astrocytes than in microglia. We provided the first analysis of LRP expression and regulation in microglia. Our results open the possibility that microglial cells could be related to the participation of LRP and its ligands in different pathophysiological states in brain.     

Functional role of the low-density lipoprotein receptor-related protein in Alzheimer's disease

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by neuronal loss, neurofibrillary tangle formation and the extracellular deposition of amyloid-beta (Abeta) plaques. The amyloid precursor protein (APP) and the enzymes responsible for Abeta generation seem to be the base elements triggering the destructive processes. Initially, the low-density lipoprotein receptor-related protein (LRP) was genetically linked to AD and later it emerged to impact on many fundamental events related to this disease. LRP is not only involved in Abeta clearance but is also the major receptor of several AD-associated ligands, e.g. apolipoprotein E and alpha2-macroglobulin. APP processing is mediated by LRP on many levels. Enhanced APP internalization through LRP decreases cell surface APP levels and thereby reduces APP shedding. As a consequence of increased APP internalization LRP enhances Abeta secretion. These effects could be attributed to the cytoplasmic tails of LRP and APP. The receptors bind via their NPXY motifs to the two PID domains of FE65 and form a tripartite complex. However, it appears that the second NPVY motif of LRP is the one responsible for the observed influence over APP metabolism. A more in-depth knowledge of the mechanisms regulating APP cleavage may offer additional targets for therapeutic intervention.     

Elevation of LDL receptor-related protein levels via ligand interactions in Alzheimer disease and in vitro

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor in the CNS that binds both apolipoprotein E (apoE) and activated alpha2-macroglobulin (alpha2M*); all 3 proteins are genetically associated with Alzheimer disease (AD). In this study we found an 85% increase in LRP levels in human AD brain frontal cortex, along with an increased level of the LRP ligands, apoE, and alpha2M. We speculated that LRP levels might be increased in response to the increased levels of its ligands, apoE, and alpha2M*. To test this hypothesis we examined the effects of alpha2M* on LRP in primary cultures. Treatment of neurons with alpha2M* significantly increased LRP levels (by 92%). This increase was prevented by coculture with receptor-associated protein (RAP), which blocks binding of LRP ligands to LRP Native alpha2M or RAP alone did not change LRP levels in vitro. We also found that alpha2M* stimulated activation of astrocytes in vitro and promoted the levels of LRP by 65%. These data indicate 1) the LRP ligand alpha2M* increases levels of LRP in primary neuronal and astrocytic cultures, 2) alpha2M*-induction of LRP levels in vitro depends on binding to LRP, and 3) LRP levels are increased in AD brain, perhaps in response to the increased levels of alpha2M.     

Increased apolipoprotein E ϵ4 in epilepsy with senile plaques

Inheritance of the apolipoprotein E (ApoE) ?4 allele is a risk factor for Alzheimer's disease (AD) and is associated with increased deposition of β-amyloid (Aβ) in AD, Down's syndrome, and normal aging. Aβ deposition in the form of senile plaques (SPs) has recently been described in patients with temporal lobe epilepsy (TLE). We studied the relationship between ApoE ?4 genotype and the deposition of Aβ in temporal lobe tissue from patients who underwent temporal lobectomy for intractable epilepsy. TLE patients with SPs had a 70% ApoE ?4 carrier frequency compared with a 27% carrier frequency among age-matched TLE controls without SPs. Our data suggest that the association between ApoE ?4 and intracerebral Aβ accumulation is not unique to the elderly or to those with dementia, and may be a feature of conditions in which there is both an ApoE ?4 allele and over-production of Aβ precursor protein, and, presumably, Aβ.     

Amyloid angiopathy in a volga german family with Alzheimer's disease and a presenilin-2 mutation (N141I)

We report the neuropathological features in 6 members of a Volga German family with autosomal dominant Alzheimer's disease linked to chromosome 1 who had a presenilin-2 mutation (N¹⁴¹I). The most significant feature in this family was the presence of severe or moderately severe amyloid angiopathy in five family members with clinical dementia. The index case with the presenilin-2 mutation had late-onset dementia at age 73 years, died of an acute intracerebral hemorrhage, and pathologically showed severe amyloid angiopathy but only rare neuritic senile plaques and neurofibrillary tangles. That she was apolipoprotein E ?2/3 heterozygous suggests that the ?2 allele may have exerted a selective protective effect resulting in late onset relatively mild Alzheimer's disease despite severe amyloid angiopathy. This family emphasizes the need for more investigation into the role of presenilin mutation in amyloid deposition, especially in the cerebral vasculature, and the role of these changes in clinical dementia.     

Down‐regulation of MET in hippocampal neurons of Alzheimer's disease brains

We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer's disease (AD) patients. Therefore, we tried to determine the cellular component‐dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up‐regulated around senile plaques, β‐amyloid deposition might be associated with astrocytosis through the HGF signaling pathway.     

Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease

Deposition of beta-amyloid (A beta), a metabolite of approximately 4 kd of the amyloid precursor protein, is a critical pathological feature in Alzheimer disease. We postulate that deposition reflects an imbalance of A beta synthesis and clearance. Several pathways that impact A beta converge on a single receptor molecule, the low-density lipoprotein receptor-related protein (LRP). This multifunctional receptor is the major neuronal receptor both for apolipoprotein E (apoE, protein; APOE, gene) and for alpha2-macroglobulin (alpha2M, protein; A2M, gene), and it mediates clearance of apoE/A beta and alpha2M/A beta complexes. The LRP also interacts with the amyloid precursor protein itself. In this review, we highlight data that support a role for LRP in A beta metabolism and hypothesize that LRP therefore plays a critical role in Alzheimer disease.     

The impact of genetic and environmental factors on the pathobiology of Alzheimer's disease: a multifactorial disorder?

Summary

Alzheimer's disease is the most common form of dementia, although its diagnosis can only be confirmed after autopsy. While 10% of cases show a family history of the disease, the remainder are sporadic. Disease-causing mutations in three genes (amyloid precursor protein and two presenilin genes) have been discovered which account for nearly all of the familial cases of Alzheimer's disease. The sporadic forms of the disease are associated with a number of genetic risk factors (apolipoprotein E, x₁antichymotrypsin, very low density lipoprotein receptor and mitochondrial DNA mutations) but none of these are either sufficient on their own or necessary for the disease. This leaves open the possibility that one or more extrinsic environmental factors may affect the progression of Alzheimer's disease. Although the evidence for specific extrinsic factors is lacking, the role of putative agents (aluminium, antioxidants, head trauma) and how they might interact with intrinsic genetic factors is discussed. Alzheimer's disease, therefore, demonstrates genetic heterogeneity and, in addition, may be considered as a multifactorial disorder.     

Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory,accumulation of Aβ, and neurodegeneration in a prodromal stage of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre‐AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N‐methyl‐D‐aspartate receptor, subunit 2A (NR2A) and the low‐density lipoprotein receptor‐1 (LRP1). PSD95 and NR2A are involved in long‐term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta‐peptide (1‐42). Aβ (1‐42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD. © 2009 Wiley‐Liss, Inc.     

Increased incidence of dementia with Lewy bodies in patients carrying the ɛ4-allele of apolipoprotein E

Background: The apolipoprotein ∈4 (APOE4) allele is a risk factor for Alzheimer's disease, but it remains undetermined whether this allele is related to the pathological development of neurofibrillary tangles (NFT) and the formation of Lewy bodies. Methods: In the present study, we examined the relationship between these changes and the APOE4 allele in 255 consecutive neuropathologically diagnosed cases. APOE genotyping was carried out by the polymerase chain reaction–restriction fragment length polymorphism method. Results: Nearly all our cases of dementia with Lewy bodies (DLB) showed the common form, having numerous senile plaques in the cerebral cortex and NFT in the parahippocampal and hippocampal regions and were also associated with the APOE4 allele. Limbic neurofibrillary tangle dementia (LNTD), characterized by the presence of NFT in limbic areas as well as the absence of senile plaques, did not appear to be associated with the APOE4 allele. Conclusions: The APOE4 allele is a risk factor for DLB as well as Alzheimer's disease and cerebral amyloid angiopathy, but not for LNTD.     

Failure to replicate a protective effect of allele 2 of NACP/α-synuclein polymorphism in Alzheimer's disease: An association study

Recently, a dinucleotide repeat polymorphism was identified in the promoter of the nonamyloid component of plaques (NACP) gene, and it was shown that the NACP allele 2 was significantly associated with healthy elderly control individuals with at least one apolipoprotein E ε4 allele, suggesting a protective role for this allele in Alzheimer's disease. We genotyped the same NACP polymorphism in a comparable number of individuals diagnosed with dementia of the Alzheimer's type and in healthy, elderly controls. In our analysis, however, no protective effect for NACP allele 2, or any of the other NACP alleles, was observed.