Rationale
Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical–neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review.

Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

La enfermedad de Alzheimer (EA) es la principal causa de demencia senil en mayores de 65 anos (60-70 por ciento), correspondiendo a la demencia multiinfarto (DMI) un 15-25 por ciento de la casuistica y un 5-10 por ciento a otras causas de demencia. Estudios epidemiologicos realizados en diversos paises demuestran que la prevalencia de la EA oscila entre un 1,9 y un 5,8 por ciento en mayores de 65 anos l . La EA parece ser ligeramente mas frecuente en mujeres que en hombres y se manifiesta mas en el medio rural que en el urban02, ademas de ser unas 2,6 veces mas frecuente en blancos que en negros3. La incidencia de EA parece ser edad-dependiente, con indices de un 1 por ciento para menores de 65 anos y de un 15-20 por ciento en mayores de 80 anos. De esta manera, al progresar la longevidad de la poblacion, la prevalencia de EA aumenta dramaticamente. Aunque la etiologia de la EA es desconocida, se han postulado varias hipotesis etiopatogenicas y factores de riesgo (tabla 1).

Neurobiología molecular de la enfermedad de Alzheimer: prospecciones terapéuticas

We report the case of a 73-year-old patient in whom a diagnosis of Creutzfeldt-Jakob disease, suggested by the clinical course, was verified by the neuropathologic finding of widespread spongiform change and astrogliosis, the presence of proteinase-resistant protein in brain extracts, and the experimental transmission of spongiform encephalopathy to primates inoculated with brain tissue. However, neuropathologic examination also revealed a profusion of senile and neuritic plaques and neurofibrillary tangles that reacted with antibody to the amyloid β-protein characteristic of Alzheimer9s disease, but not with antibody to the scrapie amyloid protein characteristic of Creutzfeldt-Jakob disease.

Coexistence of Creutzfeldt‐Jakob disease and Alzheimer's disease in the same patient

Alzheimer’s disease affects 1% of the population of the Western world and 100% of aged individuals with Down’s syndrome. It is characterized by neuronal dysfunction and depositions of. amyloid A4 protein (β-protein) in the form of intracellular neurofibrillary tangles, extracellular plaques and cerebrovascular amyloid. Amyloid A4 is a self-aggregating protein that consists of 42–43 residues. “Reverse genetics” based on the sequence of amyloid A4 protein has indicated that the amyloid protein is encoded as part of a larger protein by a gene on chromosome 21. Recent cloning studies have indicated that the amyloid precursor gene encodes at least three alternatively spliced products.

Precursor of Alzheimer’s Disease (PAD) A4 Amyloid Protein

The major protein subunit of the amyloid fibril in Alzheimer’s disease is a small molecule of 42 residues (termed A4). It is derived from a larger precursor (PreA4), the gene for which is located on chromosome 21, in close proximity to the region involved in Down’s syndrome. The predicted structure of PreA4 suggests that it is an integral membrane glycoprotein. Knowledge of the mechanisms by which PreA4 is degraded to A4 may contribute to a better understanding of the cause of Alzheimer’s disease. Similarly, the amyloid fibril in the unconventional virus diseases is composed of the PrP molecule, which in turn is derived from a neuronal membrane glycoprotein. An understanding of the process by which the PrP molecule is converted into an amyloidogenic molecule may shed some light on the nature of the infectious unit.

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases

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Precursor of Alzheimer’s Disease (PAD) A4 Amyloid Protein

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases