Volume 6, Number 1, February 2004

Pages 1-9
Alexandre de Mendonça, Filipa Ribeiro, Manuela Guerreiro, Carlos Garcia
Frontotemporal Mild Cognitive Impairment
Abstract: Mild Cognitive Impairment appears to be a heterogeneous clinical entity comprising patients in the initial phases of distinct neurological disorders. Since frontotemporal dementia (FTD) is a relatively common neurodegenerative disease with an insidious onset, it might be possible to detect the patients in the initial phases of the disorder, before being demented. In the present work we proposed a set of criteria to identify patients with mild cognitive impairment of the frontotemporal type (FT-MCI), applied these criteria retrospectively to a large patient database, and evaluated the progression of the patients.
Seven subjects fulfilling the proposed criteria for frontotemporal MCI were identified. They had symptoms of apathy, disinhibition, irritability and aggressiveness, untidiness, difficulties in decision making, obsessions and lack of concern for the others, for 1.5±0.8 years before the diagnosis of FT-MCI. Brain CT or MRI scan displayed fronto-temporal atrophy in five. Neuropsychological examination revealed deficits in tests dependent upon the frontal lobe, namely attention, verbal, motor and graphomotor initiatives and conceptual thinking. The patients kept their professional and daily activities, and were not demented.
It was possible to have the follow-up of all patients. All but one patient diagnosed FT-MCI developed dementia of the frontotemporal type within 1.8±1.0 years. Application of the proposed criteria for FT-MCI, at least in this clinical neurological setting, can identify a group of patients with a high probability of further cognitive decline to dementia of the frontotemporal type.

Pages 11-15
J. Riley McCarten, Susan J. Rottunda, Michael A. Kuskowski (Communicated by James Geddes)
Change in the Mini-Mental State Exam in Alzheimer’s Disease Over 2 Years: The Experience of a Dementia Clinic
Abstract: The decline in the Mini-Mental State Exam (MMSE) over 2 years was assessed in males with Alzheimer’s disease (AD; N=136) seen in a dementia clinic. The average initial MMSE was 21.0 (SD+/-3.9; range 14-29) and declined 2.8 points (+/-4.7; range -17 to +6) over 2 years. The mode for change on the MMSE was 0 (N=22) while the median fell between 2 and 3 points lost. Fifty-five of 136 patients (39.7%) had unchanged or better scores. There was no significant correlation between the initial MMSE and rate of change (r=0.16; p=0.06). While the progression of AD is quite variable from patient to patient, our data indicate that in most it is associated with little if any change in the MMSE even over 2 years. The MMSE is not an adequate tool to monitor change in the individual patient with AD.

Pages 17-26
A. Bilikiewicz, W.Gaus, G. Opala, A. Araszkiewicz, I. Kloszewska, L. Bidzan, K. Gustaw, J. Laczkowski, J. Georgiades
Colostrinin* (a naturally ocurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer's disease
Abstract: This study was designed to confirm or negate findings from earlier trials demonstrating that Colostrinin, a novel compound derived from ewes’ colostrum, has potential in the treatment of mild or moderate Alzheimer’s Disease (AD). 105 patients were recruited from six psychiatric centres in Poland. The trial consisted of a 15 week double-blind phase comparing Colostrinin with placebo, followed by a second 15 week open labelled phase when all patients received Colostrinin. The dosage of Colostrinin was 100ug on alternate days for three weeks followed by two weeks drug-free. This cycle was repeated three times for each phase. The primary outcome measures used were Alzheimer’s Disease Assessment Scale-cognitive portion (ADAS-cog) and Clinical Global Impression of Change (CGIC). Secondary outcome measures were Instrumental Activities of Daily Living (IADL); Mini-Mental State Examination (MMSE); ADAS-non cognitive test (ADAS-non cog); and overall Patient Response. The main outcome measures were assessed at week 15 when active was compared with placebo but all parameters were evaluated at baseline, week 15 and week 30. Two separate statistical analyses were undertaken, a Full Sample Analysis (FSA) in which all missing values were replaced with the worst result observed and a Valid for Efficacy (VFE) analysis in which those patients who had serious protocol violations were excluded. This resulted in 14 patients being excluded from the VFE-analysis. The FSA analysis at week 15 showed a stabilizing effect of Colostrinin on cognitive function in ADAS-cog (p = 0.02) and on daily function in IADL (p = 0.02). The overall patient response was also in favour of the active (p = 0.03). Patients graded as mild on entry also showed a superior response of ADAS-cog compared with more advanced cases (p = 0.01). Evidence from this study indicates an early beneficial effect on cognitive symptoms and daily function. Colostrinin has potential value in the treatment AD.
*Colostrinin is the registered trade name for a proline-rich polypeptide mixture (PRP) derived from ovine colostrum.

Pages 27-30
Daniela Ortiz and Thomas B. Shea
Apple juice prevents oxidative stress induced by amyloid-beta in culture
Abstract: Increased oxidative stress contributes to the decline in cognitive performance during normal aging and in neurodegerative conditions such as Alzheimer’s disease. Dietary supplementation with fruits and vegetables that are high in antioxidant potential have in some cases compensated for oxidative stress. Herein, we examined whether apple juice could alleviate the neurotoxic consequences of exposure of cultured neuronal cells to amyloid-ß (Aß), since at least a portion of the neurotoxicity of Aß is due to oxidative stress. Apple juice concentrate (AJC; 70 degree brix) was diluted into culture medium of SH-SY-5Y human neuroblastoma cells that had been differentiated for 7 days with 5µM retinoic acid concurrent with the addition of 20µM Abeta. AJC prevented the increased generation of reactive oxygen species (ROS) normally induced by Aß treatment under these conditions. AJC also prevented Aß-induced calcium influx and apoptosis, each of which results in part due to increased ROS. These findings suggest that the antioxidant potential of apple products can prevent Aß-induced oxidative damage.

Pages 31-43
Wieslaw K. Dowjat, Izabela Kuchna, Thomas Wisniewski, Jerzy Wegiel
A Novel Highly Pathogenic Alzheimer Presenilin-1 Mutation in Codon 117 (Pro117Ser): Comparison of Clinical, Neuropathological and Cell Culture Phenotypes of Pro117Leu and Pro117Ser Mutations
Abstract: A novel presenilin-1 (PS1) mutation (P117S) in an American pedigree is described. We compare clinical, neuropathological and cell culture phenotypes produced by this mutation with another codon 117 mutation that was earlier discovered by our group in a Polish kindred. Both mutations are associated with an unusually severe Alzheimer disease (AD) phenotype, with the onset starting before the third decade of life, rapid disease progression and acute presentation of clinical symptoms. The severity of clinical phenotype was closely correlated with the abundance of pathology: massive deposition of Aß42 in plaques, severe neurofibrillary degeneration and neuronal loss. When overexpressed in mouse neuroblastoma N2a cells, both mutations caused loss of an ability to promote neurite outgrowth and produced an increase in the ratio of secreted Aß42/40 amyloid peptides. In stably transfected N2a cell lines only mutant proteins were endoproteolytically cleaved indicating some dependability of this process on the presence of mutation. Taken together, our results show that clinical and cell culture phenotypes produced by these 2 codon 117 mutations are closely related suggesting that the pathogenic action of PS1 may involve effect on neurite outgrowth and endoproteolytic cleavage of the full-length protein. Given the high potency in vivo and in vitro of both codon 117 mutations, this site of PS1 must be particularly important for its normal/pathogenic function.

Pages 45-51
Antonella Vitali, Alessandra Piccini, Roberta Borghi, Pantaleo Fornaro, Mark A. Smith, Sandra L. Siedlak, Pierluigi Gambetti, Bernardino Ghetti, Massimo Tabaton
Soluble amyloid ß-protein is increased in frontotemporal dementia with tau gene mutations
Abstract: The relationship between senile plaques and neurofibrillary tangles, the main pathologic lesions of Alzheimer’s disease, is not completely understood. We addressed this issue examining the type and amount of amyloid ß-protein (Aß) associated with the soluble and insoluble tissue fractions in the frontal cortex of 8 cases with frontotemporal dementia with parkinsonism caused by mutations of the Tau gene (FTDP-17), in which the intracellular accumulation of polymerised tau is definitely the primary cause of neurodegeneration. As control, we examined 7 cases with frontotemporal dementia lacking distinctive histopathology (DLDH) as well as 8 pathologically normal subjects. In all cases the presence of Aß deposits was ruled out using immunocytochemistry on sections adjacent to those used for biochemical analysis. ELISA analysis showed a 2.7 and 2.1 fold (p <0.01) increase of soluble Aß42 and Aß40 in FTDP-17, compared to normal and DLDH brains, both of which had comparable levels of Aß species. Furthermore, the immunoreactivity of the intracellular Aß42 was significantly increased in cortical neurons of subjects affected with FTDP-17. The results demonstrate that the aggregation of tau protein produces an accumulation of Aß, which, however, does not reach the critical concentration needed for Aß plaques formation.

Pages 53-65
Stephen Howard Pasternak, John William Callahan, Don Joseph Mahuran (Communicated by Sharon Moalem)
The Role of the Endosomal/ Lysosomal System in Amyloid-Beta Production and the Pathophysiology of Alzheimer’s disease: Reexamining the Spatial Paradox from a Lysosomal Perspective
Abstract: One of the hallmarks of Alzheimer’s disease is the cerebral deposition of plaques composed of a 37-43 amino acid Amyloid-beta (Aß) peptide. Aß is produced by the sequential proteolytic cleavage of an integral-membrane protein, amyloid ß-protein precursor (AßPP), first by ß-secretase (BACE), and then by gamma-secretase, a complex containing presenilin and nicastrin. Although these cleavages were originally documented to occur in the endosomal/ lysosomal system, other lines of evidence suggest that the responsible proteins and activity reside in the ER or Golgi. This lack of intracellular co-localization of enzyme and substrate has been referred to as the spatial paradox of Alzheimer's disease. Here we will review the biology of the lysosome and the literature supporting the endosomal/ lysosomal production of Aß. We will also examine some of the data supporting Aß production in the biosynthetic compartments and demonstrate its compatibility with an endosomal/ lysosomal model. Finally, we will discuss the possible role of the acidic environment of the lysosome in the amyloidogenic process, and review the evidence for intracellular amyloidogenesis preceding amyloid plaque formation.

Pages 67-78
Enrico Ghersi, Pasquale Vito, Peter Lopez, Mona Abdallah, Luciano D’Adamio
The intracellular localization of Amyloid ß Protein Precursor (AßPP) Intracellular Domain Associated protein-1 (AIDA-1) is regulated by AßPP and alternative splicing.
Abstract: The Amyloid-ß Protein Precursor (AßPP) is a widely expressed transmembrane protein that is extensively processed in intracellular vesicular compartments and on the cell membrane. As a result of two sequential proteolytic cleavages, AßPP releases the Amyloid-ß (Aß) peptide, which accumulates in insoluble plaques in the brain of patients affected by Alzheimer’s disease (AD). Another peptide, a C-terminal fragment named AßPP Intracellular Domain (AID), is generated by AßPP processing and is released intracellularly. Several functions for AID have been proposed: pro-apoptotic peptide, regulator of calcium homeostasis, molecule involved in transcriptional regulation. Many intracellular proteins, such as Fe65, Jip-1, Shc, Numb and X11a, interact with AID and modulate its function by different mechanisms. Here we report the cloning and initial characterization of two isoforms of a novel protein that we named AID Associated protein-1a (AIDA-1a), AIDA-1b and AIDA-1bdeltaAnk. We show that AßPP and the AIDA-1 proteins interact in vitro, in living cells and, endogenously, in leukemia cell lines. Transfected AIDA-1a, AIDA-1b and AIDA-1bdeltaAnk localize in different compartments and the intracellular distribution of AIDA-1a can be modified by over-expression of AßPP. AIDA-1 proteins are expressed at high levels in the brain; thus, studying their involvement in AßPP processing and AID function might give new insights regarding a possible role for these molecules in normal brain development and in the pathogenesis of AD.

Pages 79-92
Leann K. Massey, Alex L. Mah, Diana L. Ford, Jaime Miller, Jing Liang, Howard Doong, Mervyn J. Monteiro
Overexpression of Ubiquilin Decreases Ubiquitination and Degradation of Presenilin Proteins
Abstract: Mutations in presenilin proteins (PS1 and PS2) are associated with most cases of early onset Alzheimer’s disease. Several proteins appear to regulate accumulation of PS proteins in cells. One such protein is ubiquilin-1, which increases levels of coexpressed PS2 protein in a dose-dependent manner. We now report that overexpression of ubiquilin-2, which is 80% identical to ubiquilin-1, also increases the levels of coexpressed PS1 and PS2 proteins in cells. To investigate the mechanism by which ubiquilin proteins increase levels of PS proteins, we examined how overexpression of ubiquilin-1, which possesses all of the key signature motifs present in ubiquilin proteins, affects PS2 gene transcription and PS2 protein turnover and ubiquitination. HeLa cells overexpressing both PS2 and ubiquilin-1 had PS2 mRNA levels lower than HeLa cells overexpressing PS2 alone, indicating that ubiquilin-1 overexpression, in fact, decreases PS2 transcription. Cells overexpressing ubiquilin-1 and PS2 displayed decreased turnover of high molecular weight (HMwt) forms of PS2 but not of full-length PS2 proteins. The reduced turnover of HMwt PS2 proteins appears to be mediated by the binding of the ubiquitin-associated domain (UBA) of ubiquilin to ubiquitin chains conjugated onto PS2 proteins. Immunoprecipitation studies indicated that ubiquilin-1 overexpression decreases ubiquitination of coexpressed PS2 proteins, suggesting that binding of ubiquilin might block ubiquitin-chain elongation. Consistent with this model, we found that the UBA domain of ubiquilin-1 binds poly-ubiquitin chains in vitro. In addition, we show that ubiquilin proteins colocalize with ubiquitin-immunoreactive structures in cells and that ubiquilin proteins are present within the inner core of aggresomes, which are structures associated with accumulation 3 of misfolded proteins in cells. Our results suggest that ubiquilin proteins play an important role in regulating PS protein levels in cells.

Pages 93-97
Joseph F. Quinn, Kathleen S. Montine, Milar Moore, Jason D. Morrow, Jeffrey A. Kaye, Thomas J. Montine
Suppression of longitudinal increase in CSF F2-isoprostanes in Alzheimer’s Disease
Abstract: We report the first longitudinal analysis of cerebrospinal fluid (CSF) F2-isoprostanes (IsoPs), quantitative in vivo biomarkers of lipid peroxidation, in patients with mild Alzheimer’s disease (AD). CSF F2-IsoPs (i) were significantly increased in patients followed over one year, (ii) correlated with some clinical indices of dementia following correction for variation in ventricular enlargement, and (iii) were significantly lower in patients who used both a-tocopherol and vitamin C.

Pages 99-105
Transcript of Live Discussion held at the Alzheimer Research Forum
Protein Folding and Neurodegeneration: Biophysics to the Rescue?

Pages 107-108
Book Review: Alzheimer: The Life of the Physician and the Career of a Disease by Konrad Maurer and Ulrike Maurer. Piper Verlag, München, Germany, 2000, 325pp. Reviewed by Gerald Münch.

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