Current Alzheimer Research Volume 1, Number 3, 2004
Alzheimer’s Disease and Immunotherapy Pp.149-163
ADAM Proteases: Protective Role in
Alzheimer’s and Prion Diseases ? Pp.165-174
Bruno
Vincent
Uncovering g-Secretase Pp.175-181
Harald
Steiner
Walnut Extract Inhibits the Fibrillization of
Amyloid Beta-Protein, and also Defibrillizes its Preformed Fibrils Pp.183-188
Neha
Chauhan, K.C. Wang, Jerzy Wegiel and Mazhar N. Malik
Lesions and Dysfunctions of the Nucleus
Basalis as Alzheimer’s Disease Models: General and Critical Overview and
Analysis of the Long-Term Changes in Several Excitotoxic Models Pp.189-214
A.
Toledano and M.I. Alvarez
Prevalence of Pathogenic Mutations in an
Italian Clinical Series of Patients with Familial Dementia Pp.215-218
S.
Signorini, R. Ghidoni, L. Barbiero, L. Benussi and G. Binetti
New Approaches in Nuclear Medicine for Early
Diagnosis of Alzheimer's Disease Pp.219-229
S.
Mirzaei, E. Gelpi, J. Booij, M. Rodrigues, I. Neumann, J. Zaknun, H. Koehn and
P. Knoll
[Back to top] Alzheimer’s Disease and Immunotherapy
Beka
Solomon
Site-directed antibodies which modulate conformation of b-amyloid peptide became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Alzheimer’s AbP, found to be a key position in protein conformation modulation, suppress formation of b-amyloid and dissolve already formed fibrillar amyloid. The performance of anti-b-amyloid antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and dissolving b-amyloid plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Naturally occurring anti-AbP antibodies have been found in human CSF and in the plasma of healthy individuals, but were significantly lower in AD patients, suggesting that AD may be an immunodeficient disorder. Active and/or passive immunization against b-amyloid peptide has been proposed as a method for preventing and/or treating Alzheimer's disease. Experimental active immunization with Ab 1-42 in humans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. Antibodies generated with this first-generation vaccine might not have the desired therapeutic properties to target the ‘correct’ mechanism, however, new clinical approaches are now under consideration. Immunotherapy represents fascinating ways to test the amyloid hypothesis and offers genuine opportunities for AD treatment, but requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.
[Back to top] ADAM Proteases: Protective Role in
Alzheimer’s and Prion Diseases ?
Bruno
Vincent
Alzheimer’s disease, as well as most of other neurodegenerative disorders, is characterized by the deposition of insoluble proteinaceous aggregates. Hence, any intervention aimed at reducing this process could be envisioned as a therapeutic way to slow down the disease. In the case of Alzheimer’s disease, the culprit protein is the 40-43 amino acidlong amyloid b peptide (Ab). This fragment is generated from the b-amyloid precursor protein (bAPP) by two distinct enzymes, namely the b- and the g-secretases. In the past years, a tremendous effort has been made to develop potent and specific inhibitors of these proteolytic activities. Beside these Ab-forming proteases, a third cleavage performed by the socalled a-secretase takes place in the middle of the Ab sequence and not only precludes its formation but also generates the secreted product sAPPa that possesses neurotrophic and neuroprotective properties. This beneficial cleavage has been shown to be strongly upregulated by protein kinase C (PKC) agonists and to be, at least partially, triggered by ADAM proteases (A Disintegrin And Metalloprotease). Recently, a proteolytic attack with similar characteristics has been shown to occur in the middle of the “toxic” 106-126 domain of the prion protein (PrPc), which PrPsc isoform is the causative agent of transmissible spongiform encephalopathies. As both Ab and PrP(106-126) trigger neurotoxicity and cell death, this ADAM-dependent proteolytic attack could represent a valuable therapeutic target in order to deplete cells from these endogenous “toxins”and prevent the associated aggregates usually detected in affected brains.
[Back to top] Uncovering g-Secretase
Harald
Steiner
Accumulation of the amyloid b-peptide (Ab) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). Ab is generated by processing of the b-amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, b-secretase and g-secretase. While b-secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of g-secretase, which catalyzes the final, intramembrane cleavage of APP as well as of several other type I transmembrane proteins, has been enigmatic for a long time. Exciting progress has been made in the past year towards its uncovering. Genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that g-secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2. Thus, the complete set of genes that is required to generate Ab from its precursor has now ultimately been identified. PS carries the active site of g-secretase and is a founding member of a novel class of polytopic aspartyl proteases that utilize a non-classical active site to cleave their membrane-tethered substrates. The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of g-secretase substrates.
[Back to top] Walnut Extract Inhibits the Fibrillization
of Amyloid Beta-Protein, and also Defibrillizes its Preformed Fibrils
Neha
Chauhan, K.C. Wang, Jerzy Wegiel and Mazhar N. Malik
Fibrillar amyloid beta-protein (Ab) is the principal component of amyloid plaques in the brains of patients with Alzheimer’s disease. We have studied the effect of walnut extract on Aß fibrillization by Thioflavin T fluorescence spectroscopy and electron microscopy. The walnut extract not only inhibited Aß fibril formation in a concentration and time- dependent manner but it was also able to defibrillize Ab preformed fibrils. Over 90% inhibition of Ab fibrillization was observed with 5 ml of methanolic extract of walnut (MEOW) both after 2 and 3 days of incubation. The maximum defibrillization (91.6%) was observed when preformed Ab fibrils were incubated with 10 ml of MEOW for 2 days. These results suggest that walnuts may reduce the risk or delay the onset of Alzheimer's disease by maintaining Aß in the soluble form. Further studies showed that anti-amyloidogenic compound in walnut is an organic compound of molecular weight less than 10 kDa, which is neither a lipid nor a protein. Chloroform extract of walnut had no effect on Ab fibrillization while MEOW and its 10 kDa filtrate inhibited Ab fibrillization equally. It is proposed that polyphenolic compounds (such as flavonoids) present in walnuts may be responsible for its anti-amyloidogenic activity.
[Back to top] Lesions and Dysfunctions of the Nucleus Basalis as Alzheimer’s Disease
Models: General and Critical Overview and Analysis of the Long-Term Changes in
Several Excitotoxic Models
A. Toledano and M.I. Alvarez
The cholinergic hypothesis of Alzheimer’s Disease (AD) has led to a number of animal models to study in vivo the pathogeny of cortical cholinergic involution. The lesion of the cholinergic neurons of the basal forebrain, especially of the nucleus basalis magnocellularis (nbm) of rodents, has been the most utilized method for obtaining these models. Toxic substances such as quinolic, kainic, NMDA, ibotenic and quisqualic acids, the specific cholinergic toxin AF64, amyloid, and antibodies to neurotrophic factors; etc, have been used to produce such lesions. These investigations have helped our understanding of the role of cerebral cholinergic innervation in cognitive disorders and their treatments. However, this research has provided conflicting results, and much controversy has developed surrounding the role of the cholinergic systems and the suitability of these models. It is very important to take into account the exact type of nbm/cortical lesion produced, and its evolution, if meaningful results are to be obtained. This review covers the theoretical and practical use of nbm lesion models, and examines the main positive and negative results obtained by different authors in the light of our own observations on the long-term (3 years) morphological and biochemical changes that occur in several kinds of nbmlesion model rats. The changes seen were very different, but many of them were increased up to the end of life with no clear relationship with the development of the original lesion.
[Back to top] Prevalence of Pathogenic Mutations in an
Italian Clinical Series of Patients with Familial Dementia
S.
Signorini, R. Ghidoni, L. Barbiero, L. Benussi and G. Binetti
Genetic factors are involved in the aetiology of dementias. Three genes have been identified which, when mutated, cause Familial Alzheimer disease (FAD): the presenilin-1 (PS1), the presenilin-2 (PS2) and the amyloid precursor protein (APP) genes. Together, these mutations are responsible for 30-50% of the cases with autosomal dominant Alzheimer disease (AD), and for about 5% of all AD cases. While over 130 mutations have been identified in PS1, mutations in PS2 and APP are rarer, since only 10 and 22 mutations, respectively, have been found in these FAD genes. Instead, mutations in the MAPT gene were associated with Familial Frontotemporal dementia (FFTD) linked to chromosome 17 (FTDP-17). Frontotemporal dementia (FTD) can occur in a sporadic form, but in 30-50% of cases there is a positive family history of dementia.
In this study, we determined the spectrum of mutations and the relative contribution of the above mentioned four genes in our Italian clinical series of patients with a positive family history of dementia.
[Back to top] New Approaches in Nuclear Medicine for Early Diagnosis
of Alzheimer's Disease
S.
Mirzaei, E. Gelpi, J. Booij, M. Rodrigues, I. Neumann, J. Zaknun, H. Koehn and
P. Knoll
Dementia, Alzheimer’s disease (AD) being the most common cause of it, is a major and growing medical and social problem, particularly in the advanced age, with the highest rate in the population over 75 y. Recent sophisticated therapeutic measures require more sensitive diagnostic tests to recognize early stages of the disease. In this paper, the current neuronuclear imaging literature is reviewed with regard to early and differential diagnosis of dementia. Functional imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) could provide the clinician with additional information complementary to morphological assessments, thus contributing to achieve a more adequate diagnosis, and also with information regarding prodromal stages of AD.