S264 Poster Presentation: Neuropathology IV

Poster Presentation: Neuropathology IV

OXIDATIVE STRESS AND MITOCHONDRIA ALTERATIONS IN ALZHEIMER’S DISEASE.

Oxidative stress may play an Important role in pathogenetic mechanisms of Alrhei-

err’s disease. The morphology of the mitochondria is closely associated with teh

formation of free oxigen radicals. In an extensive unltrastructural study of ten brains

from patiens suffered Alrheimer’s disease, we tried ot analyse morphologically and

morphometricaly the mitochondria in neurons of the hippocampus, the frontal adn

par&al cortex, the putamen, the thalamus and the F’urkinje cells of the cerebellar

hemispheres. The morphological alteration\ of the mitochondria mostly consisted of

changes of the cristae and rough accumulations of osmiophilic material. Neurons

which contained paired helical filaments (PHFs) demonstarted large number of small

round mitochondria with marked disorganization of their interior structure. Mitochon-

drial alterations were also prominent in neurons, which showed loss of dendritic

branches, resulting in abreviation of the dendritic field. Mitochondrial alteration\

were illso been in neurons which demonstrated minimal cytoskeletal alteration\. wch

a\ the Purkinje cells in the cerebellar cortex and the large neurons of the lateral

thalamic nuclei. The morpological and morphometric alteration of the mitochrondria

m Alzheimer’s disease may cintribute in plotting part of the broad etiopathological

background of the dlcease.

PROGRESSIVE CHANGES IN AMYLOID, APOLIPOPROTEIN-E, SYNAPTIC MARKERS AND UBIQUITIN IN FRONTAL LOBE OF PROSPECTIVELY STUDIED ELDERLY HUMANS.

AIteratIons in a number of neuronal proteins occur during Alzheimer’r d&ease (AD).

To evaluate neuronal protein changea in AD pathogen&s. we quantlfxd A/340.

AP42, ApoE, ubiquitin, synuclein and \ynaptophysin in postmortem frontal lobe

samplea from prospectively studted individuals of the Religious Order\ Study by

quantitative immunoassays. Cases were grouped by diagnostic category for analysis:

AD (N=h), mild cognitive impairment (MCI) (N=9) and no cognitive impairment

(NCI) (N=9). Monoclonal antibodies to amyloid (BANSO, BCOS. BA27. 4G8).

ubiqultin (Ubi-I), ApoE (MABlO62) and 5ynaptophysin (EPIO) and a polyclonal

antibody to synuclein were used. We found I) AP42 level\ increased and an estimate

of the amount of N-terminal truncated A@ (P3) decreaxd acrou diagnostic categories

(NC1 to MCI to ADI. hut only the differences between AD and NCI were sigmficant

tP<0.05). 2) ApoE mcreased with increasing AP and was higher in AD than both

MCI and NCI, but again AD was only \ignilicantly dtfferent from NCI. 3) Insoluble

and prewmahly conJugated ublquitm was significantly higher in AD than MCI

(PiO.05) and NC1 (P<O.O05), while wluble ubiquitin was lower m AD than NC1

(P<O.O5), but not MCI (P=O.O75). 4) The levels of synuclem were significantly

reduced in both AD and MCI compared to NC1 (AD vs NC1 PcO.05; MCI vb NC1

P<O.OOl). 5) Like synuclein, synaptophyain also decreased across dlagnoatic cate-

gories, but the only significant difference wa\ between AD and NC1 (PiO.O.5). These

data suggest that AD pathogen&s is associated with progreraive accumulation of full

length amyloid and ape-E along with decreases in N-terminal truncated amyloid.

Neurodegeneration i\ marked by decreases in synaptic markers and increases in

ubiquitm conjugate?. AD is quantitatively most different from NCT, with MCI

intermediate for most measure?. Thi\ i\ con%tent with the idea that MCI may be a

precursor to AD. It” MCI were a heterogeneous classification, it might also account for

greater variance m the measures and less significant differences between AD on one

hand and NCI on the other. Biochemical analyses may assist in understanding

progressive age-related brain changes and the nature of MCI.

11211( OSTROGN RECEPTORS CONTAINING NEURONS DECREASE IN THE HIPPOCAMPUS OF ALZHEIMER PATIENTS

l%trogens are considered to be involved in the pathogenesis of Alzheimer’s disease.

In the present study, the immunocytochemical localisation of estrogen receptor -a and

-p (ER-a and ERP)exprewng neurons in the human hippocampus of AD patient5

were compared with age and sex matched controls. Exammation of the cell\ in

hippocampus revealed distinct cellular exprewion patterns of ER-a and ER-P. Overall

more neurons expressed ER-a than ER-P in the hippocampu\. Staining for ER-a was

strongest in the cell nucleus of pyramidal neurons while also a weak cytoplasmic

staming was seen. In contrast, ER-P immunoreactivity was more pronounced in the

cytoplasm. Astrocyte-like cells immunoreactive for ER-a were noted around blood

vessels, in the neuritic plaques and in the subependymal region. Neuronal proceaaes

(axons and dentrites) showed immunoreactivity for both ER-cu and ER-P. The number

of ER-a expressing neurons was significantly lower in the hippocampus of patient\

with AD than in controls. There was also less ER-a and ER-P immunoreactive

neuronal process in the hippocampus in AD patients. More aatrocyte-like cells

immunoreactive for ER-a were presented in AD patients than in controls. More ER-a

neurons were seen in the CA3 region than tn CA1 region while interestingly, more

silver staining plaques and tangles were found in the CA1 than in the CA3 region. In

conclusion, both ER-a and ER-@ exprtxing neurons were found in the human

hippocampus. The number of ER-u neurons was lower in the hippocampus of AD

patients. These data are conststent with the proposed involvement of estrogens in the

pathogen&\ of AD. Brain maternal was provided by the Netherlands Brain Bank

(Coordinator: Dr. R. Ravid).

MOLECULAR PATHOLOGICAL STUDIES OF NEUROFIBRIL- LARY TANGLE-PREDOMINANT FORM OF DEMENTIA

The neurofihrillary tangle-predominant form of dementia (NFTD) is characterized by

abundant neurofibrillary tanglea (NFT) in the mesolitnbic area, accompanied by only

low numbers of senile plaque, (SP). NFTD has usually been reported in very old

demented Cubjects but, also occur\ in familial tauopathy with a mutation in the tilu

gene. We conducted a detailed molecular pathological Investigation of a caw of

NFTD with the R406W tau mutation and three case!, of NFTD wtthout tau mutation

to determine if any aigniticant neuropathological differences could be identified

between these two types of NFTD. In all cases, immunocytochemical studies with

AT8 and Gallyas-Braak silvet- staining revealed positive staining on wbpial astro-

cyta, astrwytic plaques, tuft-shaped aatrocyte\, oligodendroglial coiled bodies and

numerous threads in the temporal subcortical white matter. Our results suggest that

cases of the R406W mutation and NRD without the tau gene mutation may share a

common final pathway ti,r the processing of the tau protein.

11213] “RISK FACTORS” AND HISTOPATHOLOGICAL HALLMARK LESIONS OF ALZHEIMER’S DISEASE INCLUDING P-AMY- LOID LOAD IN AGING AND DEMENTIA

Post-mortem brain tissue sampled to the Kuopuo Brain Bank since 1991 was analyzed

utilizing histochemical, immunohistochemical and morphometrical methodology. 730

cases were available, 200 with clinical aigns of dementia. Of the 530 non-demented

40% were females, 16% had diabetes, the mean age at death war 69 years, 30%

camed one or two coptes of ApoE ~4 allele, the cardiovascular tndex (CVI) estimated

at autopsy was 8.3 (range O-15) and the u2M distribution was AA-2Y%, AG-53% and

GG-18%. In the demented group the mean age at death was 7Y, 7.5% were females.

IO% had diabetes, 55% carried ApoE t4 allele, the mean CVI was 7.6 and the a2M

genotype distribution was AA-28% AG-49% and GG-23%. When all cases wtth

\enile/neuritic plaques (SP/NP) were (314 of 73O)included disregarding the clmical

symptomatology. the score of SP/NP’s was influenced significantly by the age at

death (p<O.Ol), by gender(p<0.(lOl),by diabeter (p<O.Ol, by ApoE genotype

(p<O,OOl) and by CVI (p<O.Ol). a2M genotype did not influence the extent ol

SP/NP’s in neocottex. When all cases with neurotibrillary tangles (NFT)were (146 of

730) Included disregarding the clinical qymptomatology, ApoE genotype (p<O.O03)

and diabetes (p<O.O3) were shown to significantly be related to the scores of NFTs.

On the other hand age at death, gender, CVI or a2M genotype displayed no

rignificant influence on the extent of NFT‘a in neocottex. When all cases wth

P-amyloid (PA) aggregates were (345 of 730) included (stained area fractmn > 0)

disregarding the clinical aymptomatology. age at death (p<O.OOl), gender (p< 0.001,

diabetes (pi0.04)and ApoE genotype (p<O.OOl) were shown to rignificantly

influence the load of PA in neocortex. Contrary to this the CVI and o12M genotype

lacked any influence on the PA load. Our results indicate that indeed age at death

(increase with age), gender (female > male) and ApoE genotype (~4 allele > c3

allele) are risk factors concidering the histopathological hallmark lesions of AD

m&ding PA aggregates. In patient5 wffering from diabetes the extent of Iwon~ wa\

lower compared to those without this “risk factor”. CVI intluenced only the score of

SP/NP’\ and n2M lacked any influence on the analyzed lesions.