Current Alzheimer Research - Volume 1, Issue 3, 2004

Alzheimer's disease (AD) respects not privilege, rank, nor fame. It is among the great equalizers that strike where they will and reveal the fundamental human unity we all share. In November of 1994, the world was shown this when Ronald Reagan, 40th president of the United States of America, announced that he had been diagnosed as a likely case of AD [1]. As of June of 2004, his long struggle has ended. He announced his diagnosis already having weathered ridicule based upon worn-out prejudices regarding age and mental capacity. His publication of his AD diagnosis takes on all the more meaning in such light-even though Mr. Reagan had already experienced the stereotypes many elderly have to endure regarding their mental competency, he stepped up and willingly became a target and a banner. In association with the Alzheimer's Association, Mr. and Mrs. Reagan formed the Ronald and Nancy Reagan Research Institute in 1995, dedicated specifically to funding basic science research on mechanisms and molecules associated or potentially linked with AD [2]. Nancy Reagan has since been tireless as an advocate of AD research, including speaking publicly at a benefit for the Juvenile Diabetes Research Foundation in favor of US government support of stem cell research [3], a stand which may have put her at odds with long-term political allies. Their daughter, Maureen Reagan, was committed to the cause of AD research, serving as a board member for the Alzheimer's Association from 1999 to her death from melanoma in 2001. Her duties were taken up by her husband, continuing the Reagan family legacy of support for AD research. She has also testified before the US Congress regarding AD and served as an honorary chair for the Alzheimer's Association's Memory Walk from 1997 to 2000. In 2000 she received the Alzheimer's Association's Distinguished Service Award [2]. Ronald Reagan was diagnosed in his eighth decade of life and managed to survive nearly a decade with the condition. This is more than double the median survival time after diagnosis reported for male patients in one recent study [4]. While this may point to what can currently be done when a patient fully acknowledges and seeks treatment for AD as soon as a diagnosis is reached, it also should bring to mind that current treatments, which slow but neither halt nor reverse AD progression, cannot lift the significant burden that AD puts on caregivers [4, 5]. This burden is not merely financial, but is, in the words of Nancy Reagan, “a truly long, long good-bye” [6]. In essence, a caregiver must deal with watching a loved one die twice: “There are so many memories I can no longer share, which makes it very difficult. When it comes right down to it, you're in it alone.”[6] Currently available treatments do no more than postpone the sentence that AD inflicts on its victims. We as AD researchers are caught short and humbled by every decline due to AD and the part the disease plays in a patient's death, and more especially, the inevitability of AD's progression, even with complete access to the best therapies we have been able to offer. Indeed, in an ultimate sense, AD can be said to not only give no respect to rank, but precious little to treatment. It is this basic shortcoming of our current methods that saddens us most regarding the decline and death of Ronald Reagan, that it was inevitable despite our best efforts. This is not to say there is no hope. Tremendous research is currently underway in basic science and clinical settings to understand the pathobiology, genetics, and patient care issues of AD in order to find novel strategies for treatment of Alzheimer's disease. To this end, a new journal, Current Alzheimer Research, has been started. This peer-reviewed research journal “is meant to disseminate up-to-date knowledge in different aspects of current AD research” [7]. Nevertheless, the difficulties they faced only served to drive Mr. Reagan and his family to redouble their efforts to see to it that researchers received the funding needed and the public receive the education needed to deal with Alzheimer's disease, not only as a current problem, but to seek its causes, seek more effective treatments, and possibly find a means to eradicating it. Therefore, we dedicate this, the third issue of Current Alzheimer Research, to Ronald W. Reagan, 40th president of the United States of America and unashamed AD patient, to Mrs. Nancy Reagan, AD caregiver, survivor, and advocate, and to Ms. Maureen Reagan.

Site-directed antibodies which modulate conformation of β-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 AβP, found to be a key position in protein conformation modulation, suppress formation of β-amyloid and dissolve already formed fibrillar amyloid. The performance of anti-β-amyloid antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and dissolving β-amyloid plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Naturally occurring anti-AβP 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 β-amyloid peptide has been proposed as a method for preventing and / or treating Alzheimer's disease. Experimental active immunization with Aβ 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.

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 (Aβ). This fragment is generated from the β-amyloid precursor protein (bAPP) by two distinct enzymes, namely the β- and the γ-secretases. In the past years, a tremendous effort has been made to develop potent and specific inhibitors of these proteolytic activities. Beside these Aβ-forming proteases, a third cleavage performed by the socalled α-secretase takes place in the middle of the Aβ sequence and not only precludes its formation but also generates the secreted product sAPPα 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 “toxicrdquo; 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.

Accumulation of the amyloid β-peptide (Aβ) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). Aβ is generated by processing of the β-amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, β-secretase and γ-secretase. While β-secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of γ-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 γ-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 Aβ from its precursor has now ultimately been identified. PS carries the active site of γ-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 γ-secretase substrates.

Fibrillar amyloid beta-protein (Aβ) 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 Aβ preformed fibrils. Over 90% inhibition of Aβ 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 Aβ 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 Aβ fibrillization while MEOW and its 10 kDa filtrate inhibited Aβ fibrillization equally. It is proposed that polyphenolic compounds (such as flavonoids) present in walnuts may be responsible for its anti-amyloidogenic activity.

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.

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.

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.