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At least 19 recordsLinked to original sources

PubMed2005

The amyloid pathology progresses in a neurotransmitter-specific manner.

Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

Acetylcholine↗

PubMed2006

Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.

gamma-Secretase processing of the amyloid precursor protein (APP) generates Abeta40 and Abeta42, peptides that constitute the principal components of the beta-amyloid plaque pathology of Alzheimer's disease (AD). The gamma-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced gamma-secretase cleavage at the Abeta40, but not the Abeta42, site. Surprisingly, this reduction of Abeta40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in gamma-secretase processing, and decreased Abeta40, not increased Abeta42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Abeta40 against amyloid pathology and raises the possibility that impaired gamma-secretase activity could be the basis for AD pathogenesis in general.

Amino Acid Sequence↗

PubMed2003

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.

BACKGROUND: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. OBJECTIVE: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. METHODS: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. RESULTS: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. CONCLUSIONS: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Adult↗

PubMed2003

Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology.

While the cholinergic depletion in Alzheimer's disease (AD) has been known for some time, a definitive involvement of other neurotransmitter systems has been somewhat more elusive. Our study demonstrates a clear involvement of both glutamatergic and, to a lesser extent, GABAergic neurons in an early onset transgenic mouse model of AD-like amyloid pathology. Immunohistochemical staining and subsequent quantification has revealed a statistically significant increased density of glutamatergic and GABAergic presynaptic boutons in both the plaque free and plaque adjacent cortical neuropile areas of transgenic mice as compared to non-transgenic controls. Furthermore, amyloid plaque size was shown to have a statistically significant effect on the relative area occupied by dystrophic glutamatergic neurites in the peri-plaque neuropile. These findings support our hypothesis that the amyloid pathology progresses in a time and neurotransmitter specific manner, first in the cholinergic system which appears to be most vulnerable, followed by the glutamatergic presynaptic boutons and finally the somewhat more resilient GABAergic terminals.

Alzheimer Disease↗

PubMed2002

NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases.

Approximately 60% of familial and sporadic Alzheimer's disease (AD) cases manifest Lewy bodies (LBs), of which a major component is alpha-synuclein. Although the pathogenic role of alpha-synuclein in AD remains unclear, LB formation might be associated with pathological beta-amyloid (Abeta) overproduction. Here, we present the clinical and pathological characteristics of two affected family members from a pedigree with the E184D mutation of presenilin-1. One case presented with typical clinical features of AD, but the other case also developed clinical characteristics of dementia with Lewy bodies (DLB), including visual hallucinations, delusions, and parkinsonism. In both cases, neuropathological examination revealed numerous neurofibrillary tangles and severe Abeta deposition in senile plaques and amyloid angiopathy, in which Abeta42 rather than Abeta40 was predominant. Furthermore, remarkable alpha-synuclein pathology, including LBs and the accumulation of the non-Abeta component of AD amyloid (NAC) in plaques and astrocytes, was detected only in the case that presented with the symptoms of DLB. These findings suggest that (1) LB pathology can influence the clinical features of familial AD, (2) the E184D mutation of presenilin-1 may be associated with the LB formation through Abeta overproduction, although the process of LB formation is strongly affected by other unknown mechanisms, (3) in neurodegenerative disorders with LBs, there is a common pathophysiological background inducing NAC accumulation in neuritic plaques and astrocytes, and (4) the NAC accumulation in neuritic plaques is modulated by the abnormally aggregated tau protein.

Adult↗

PubMedDate not supplied

The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice.

Metals such as zinc, copper and iron contribute to aggregation of amyloid-beta (Abeta) protein and deposition of amyloid plaques in Alzheimer's disease (AD). We examined whether the lipophilic metal chelator DP-109 inhibited these events in aged female hAbetaPP-transgenic Tg2576 mice. Daily gavage administration of DP-109 for 3 months markedly reduced the burden of amyloid plaques and the degree of cerebral amyloid angiopathy in brains, compared to animals receiving vehicle treatment. Moreover, DP-109 treatment appeared to facilitate the transition of Abeta from insoluble to soluble forms in the cerebrum. These results further support the hypothesis that endogenous metals are involved in the deposition of aggregated Abeta in brains of AD patients, and that metal chelators may be useful therapeutic agents in the treatment of AD.

Aging↗

PubMed2006

Neuronal or glial expression of human apolipoprotein e4 affects parenchymal and vascular amyloid pathology differentially in different brain regions of double- and triple-transgenic mice.

Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble Abeta40 and Abeta42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the Abeta42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy.

Amyloid beta-Protein Precursor↗

PubMed2006

Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology.

The incidence of Alzheimer's disease (AD) is greater in women than men at any age, as is the development of amyloid pathology in several transgenic mouse models of AD. Due to the involvement of metals in AD pathogenesis, variations between the sexes in metal metabolism may contribute to the sex difference in AD risk. In this study, we investigated sex differences in brain metal levels across the lifespan in mice of two different background strains, as well as in mice overexpressing the human amyloid precursor protein (APP) and amyloid-beta protein (Abeta). We demonstrate consistently lower Cu and higher Mn levels in females compared with males at any age studied. The sex differences in Cu and Mn levels are independent of APP/Abeta expression. AD brain exhibits decreased Cu and increased Mn levels, as do transgenic mice overexpressing APP or Abeta. The age-dependent elevations of Cu, Fe and Co levels were found to be significantly greater in mice of B6/SJL background compared with B6/DBA. If depleting Cu and/or rising Mn levels contribute to AD pathogenesis, natural sex differences in these brain metal levels may contribute to the increased propensity of females to develop AD.

Alzheimer Disease↗

PubMedDate not supplied

Mild amyloid pathology in the primary visual system of nonagenarians and centenarians.

In order to study the patterns of Alzheimer disease (AD)-related pathology in the primary visual system of the oldest old, we performed a quantitative analysis of senile plaques (SP), diffuse beta amyloid (A beta) deposit and neurofibrillary tangle (NFT) distribution in primary area 17, and a semi-quantitative analysis in the dorsal lateral geniculate nucleus (LGN), lateral inferior pulvinar (LIP) and superior colliculus (SC) of 21 individuals aged between 93 and 102 years. Among them, 10 cases were considered as non-demented (ND), while 9 presented very mild cognitive impairment (VMCI), and 2 cases had a clinical diagnosis of AD. Silver methenamine and Gallyas staining, A beta and tau immunostaining revealed the distribution of AD lesions. In primary area 17, most cases, either ND or with VMCI displayed a low to medium number of SP. There was no significant difference in SP and A beta deposit densities between ND and VMCI groups. On the whole, 0.4--2.4% of the cross-sectional cortical area was covered with A beta deposits. Only 6 cases, either ND or with VMCI, were totally devoid of SP and diffuse A beta deposits. Among the subcortical structures, the LIP and SC exhibited low densities of SP and A beta deposits in about half of the ND and VMCI cases, while the LGN was totally spared. NFT were almost absent in area 17 and subcortical nuclei of ND and VMCI cases. These data imply that the ageing of the primary visual system in ND and VMCI nonagenarians and centenarians is characterised by the frequent development of mild amyloid pathology in area 17 in the absence of NFT. In agreement with previous studies in very old cohorts, they also suggest that amyloid deposition is not related to the early stages of the dementia process in the oldest old.

Aged↗

PubMed2002

The effects of long-term treatment with metrifonate, a cholinesterase inhibitor, on cholinergic activity, amyloid pathology, and cognitive function in APP and PS1 doubly transgenic mice.

Recent studies in cell cultures have shown that modulating the cholinergic activity can influence the processing and metabolism of amyloid precursor protein (APP). To investigate whether acetylcholinesterase inhibitors (ChEIs) could decrease production of amyloid beta-peptide (A(beta)) and slow down the accumulation of A(beta) also in vivo, we chronically administered metrifonate (100 mg/kg, po), a second-generation ChEI, to 7-month-old doubly transgenic APP+PS1 mice and their nontransgenic littermate controls for 7 months. Behavioral studies, including open field test, T maze, and water maze, were conducted after 6 months treatment with metrifonate, and the mice were sacrificed at the age of 14 months for biochemical and histological analyses. The long-term treatment with metrifonate failed to inhibit the marked overproduction and deposition of A(beta) in the APP+PS1 mice; in contrast, it increased both A(beta)40 and A(beta)42 levels in the hippocampus. However, the A(beta)42 to 40 ratio was significantly reduced by the treatment. In addition, the number of amyloid plaques in the hippocampus did not differ between the treatment and the control groups. Tolerance to cholinesterase inhibition might be induced in the mouse brain because the inhibition rate of AChE was attenuated from about 80 to 50% during the experiment in both APP+PS1 and nontransgenic mice. The metrifonate treatment did not affect cognitive testing parameters but reduced swimming speed and locomotor activity in both genotypes. Our results do not support the idea that ChEIs would slow down the progression of amyloid pathology in Alzheimer's disease.

Alzheimer Disease↗

PubMed2000

Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations.

Hereditary frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is associated with different mutations in the microtubule-associated protein (MAP) tau gene. Pathological changes consist of accumulation of hyperphosphorylated tau protein in frontal and temporal cortex, hippocampus, and some subcortical nuclei. We describe the neuropathological findings in five patients with P301L mutation, and in two affected sibs with R406W mutation. The P301L brains all showed a pretangle-type tauopathy of the frontal and temporal cortices. One of these patients, however, also showed an Alzheimer-type tauopathy with neurofibrillary tangles (NFT), neuritic plaques, and amyloid angiopathy of the temporoparietal cortex. Three tau bands (64, 68, and 72 kDa) were seen in the frontal cortex, while the temporal cortex revealed four bands (60, 64, 68, and 72 kDa), containing all six tau isoforms. The first R406W brain showed many NFT in affected regions with only a few diffuse amyloid plaques. The second R406W brain contained a much higher density of NFT in affected regions, and an extensive amyloid deposition consisting of both diffuse and neuritic plaques with dense cores. An intriguing question is whether the FTD and Alzheimer disease changes are concomitant, or whether there is an interaction between tau and amyloid pathology. An acceleration of NFT formation due to amyloid deposition has been observed in nondemented aging and preclinical AD. The question whether this mechanism occurs in FTD with tau mutations remains to be elucidated.

Aged↗

PubMed2004

Frontal lobe volume, function, and beta-amyloid pathology in a canine model of aging.

Application of magnetic resonance imaging (MRI) techniques reveals that human brain aging varies across cortical regions. One area particularly sensitive to normal aging is the frontal lobes. In vitro neuropathological studies and behavioral measures in a canine model of aging previously suggested that the frontal lobes of the dog might be sensitive to aging. In the present study, MRI scans were acquired to compare age-related changes in frontal lobe volume with changes in executive functions and beta-amyloid pathology in the frontal cortex of beagle dogs aged 3 months to 15 years. Decreases in total brain volume appeared only in senior dogs (aged 12 years and older), whereas frontal lobe atrophy developed earlier, appearing in the old dogs (aged 8-11 years). Hippocampal volume also declined with age, but not occipital lobe volume past maturity. Reduced frontal lobe volume correlated with impaired performance on measures of executive function, including inhibitory control and complex working memory, and with increased beta-amyloid accumulation in the frontal cortex. Age-related hippocampal atrophy also correlated with complex working memory but not inhibitory control, whereas occipital lobe volume did not correlate with any cognitive measure. These findings are consistent with the frontal lobe theory of aging in humans, which suggests that the frontal lobes and functions subserved by this region are compromised early in aging.

Aging↗

PubMed2006

Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology.

Mutations in presenilin 1 (PS1) lead to dominant inheritance of early onset familial Alzheimer disease (FAD). These mutations are known to alter the gamma-secretase cleavage of the amyloid precursor protein, resulting in increased ratio of Abeta42/Abeta40 and accelerated amyloid plaque pathology in transgenic mouse models. To investigate the factors that drive the Abeta42/Abeta40 ratio and amyloid pathogenesis and to investigate the possible interactions between wild-type and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1M146V/+) or PS1 null (PS1M146V/-) background and crossed these alleles with the Tg2576 APP transgenic mice. Introduction of the PS1 M146V mutation on Tg2576 background resulted in earlier onset of plaque pathology. Surprisingly, removing the wild-type PS1 in the presence of the PS1 M146V mutation (PS1M146V/-) greatly exacerbated the amyloid burden; and this was attributed to a reduction of gamma-secretase activity rather than an increase in Abeta42. Our findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.

Alzheimer Disease↗

PubMed2004

The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease.

Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.

Adrenal Glands↗

PubMed2001

Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology.

The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the mammalian brain in three different isoforms, two constitutive enzymes (i.e., neuronal, nNOS, and endothelial eNOS) and one inducible enzyme (iNOS). All three isoforms are aberrantly expressed in Alzheimer's disease giving rise to elevated levels of nitric oxide apparently involved in the pathogenesis of this disease by various different mechanisms including oxidative stress and activation of intracellular signalling mechanisms. It still is a matter of debate, however, whether the abnormal expression of NOS isoforms has some primary importance in the pathogenetic chain and might thus be a potential therapeutic target or only reflects a secondary effect that occurs at more advanced stages of the disease process. To tackle this question, we analysed the expression of both eNOS and iNOS in patients with sporadic AD, in transgenic mice expressing human amyloid precursor protein (APP) with the Swedish double mutation under control of the Thy1 promotor (APP23 mice), and after electrolytic cortical lesion in rat, an experimental paradigm associated with elevated expression of APP. In all three conditions, an astrocytosis was induced accompanied by a strong increase of both iNOS and eNOS. Both NOS isoforms were frequently though not always colocalized. Thus, based on the expression pattern of NOS isoforms three types of astrocytes, expressing only one of the two isoforms or both together could be distinguished. In both AD and transgenic mice eNOS-expressing astrocytes exceeded iNOS-expressing astrocytes in number. Astrocytes with elevated levels of iNOS or eNOS were constantly seen in direct association with Abeta-deposits in AD and transgenic mice and were found in the vicinity of the lesion site in the rat cortex. The results of the present study show that expression of both iNOS and eNOS is increased in activated astrocytes under experimental conditions associated with elevated expression of APP (electrolytic brain lesion) or Abeta-deposition (APP23 transgenic mice). Therefore, it is suggested that altered expression of these NOS isoforms being part of AD pathology is secondary to the amyloid pathology and might not be primarily involved in the pathogenetic chain though it might contribute to the maintenance, self-perpetuation and progression of the neurodegenerative process.

Aged↗

PubMed2005

Lentiviral vector-based models of amyloid pathology: from cells to animals.

Lentiviral vectors are efficient tools for the introduction of genes into a wide range of established and primary cells in vitro, ex vivo, and in vivo, and also permit efficient transgenesis in a wide range of mammalian species. Our goals have been to apply the broad capabilities of the lentiviral vector system to AD research. Using a set of vectors expressing APP and PS1 genes, we demonstrated the efficiency and fidelity of the system for in vitro biochemical analyses of genes and pathways involved in plaque deposition. These analyses were performed in cell lines and in primary neuronal cultures, which have previously been difficult to use. The methods and tools described here are applicable to the study of effects of other genes and gene combinations on APP processing, including suppression of gene activity by delivering shRNAs. We have attempted to create local plaque pathology by stereotactic injection of APP and PS1 expressing vectors into mouse brains for use as a rapid model for plaque pathology that can be used in a broad range of mammals. No amyloid or preamyloid pathology has been detected over a six-month period; the possible reasons are discussed. Lastly, we have used the vectors to create transgenic rats expressing mutant APP and mutant PS1 and have obtained the first set of positive pups with more expected. The results presented here demonstrate the utility of Lentiviral vector-based approaches to the study of AD and other neurodegenerative diseases.

Amyloid beta-Protein Precursor↗

PubMed2025

Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer's Disease Model.

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.

Alzheimer’s disease↗

PubMed1999

Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and beta-amyloid pathologies.

Investigation of the integrity of the ryanodine receptor in Alzheimer's disease is important because it plays a critical role in the regulation of calcium release from the endoplasmic reticulum in brain, impairment of which is believed to contribute to the pathogenesis of Alzheimer's disease. The present study compared ryanodine receptor levels and their functional modulation in particulate fractions from control and Alzheimer's disease temporal cortex, occipital cortex and putamen. Relationships between ryanodine receptor changes and the progression of Alzheimer's disease pathology were determined by examining autoradiographic [3H]ryanodine binding in entorhinal cortex/anterior hippocampus sections from 22 cases that had been staged for neurofibrillary changes and beta-amyloid deposition. A significant (P < 0.02) 40% decrease in the Bmax for [3H]ryanodine binding and significantly higher IC50 values for both magnesium and Ruthenium Red inhibition of [3H]ryanodine binding were detected in Alzheimer's disease temporal cortex particulate fractions compared to controls. Immunoblot analyses showed Type 2 ryanodine receptor holoprotein levels to be decreased by 20% (P < 0.05) in these Alzheimer's disease cases compared to controls. No significant differences were detected in [3H]ryanodine binding comparing control and Alzheimer's disease occipital cortex or putamen samples. The autoradiography study detected increased [3H]ryanodine binding in the subiculum, CA2 and CA1 regions in cases with early (stage I-II) neurofibrillary pathology when compared to Stage 0 cases. Analysis of variance of data with respect to the different stages of neurofibrillary pathology revealed significant stage-related declines of [3H]ryanodine binding in the subiculum (P < 0.02) with trends towards significant decreases in CA1, CA2 and CA4. Post-hoc testing with Fisher's PLSD showed significant reductions (74-94%) of [3H]ryanodine binding in the subiculum, and CA1-CA4 regions of the late isocortical stage (V-VI) cases compared to the early entorhinal stage I-II cases. [3H]Ryanodine binding also showed significant declines with staging for beta-amyloid deposition in the entorhinal cortex (P < 0.01) and CA4 (P < 0.05) with trends towards a significant decrease in the dentate gyrus. We conclude that alterations in ryanodine receptor binding and function are very early events in the pathogenesis of Alzheimer's disease, and may be fundamental to the progression of both neurofibrillary and beta-amyloid pathologies.

Adult↗