Alzheimers Disease Pathogenesis Models and Experimental Therapeutics

Donald L. Price1'2'3, TongLi1'3, Fiona M. Laird1'3, MohamedFarah1'3, Alena V. Savonenko1, Michael Lee2 ,Juan Troncoso1'2'3, and Philip C. Wong1'2'3

Alzheimer's Disease (AD) is associated with progressive impairments of memory and cognition, genetic causes/risk factors, characteristic neuropathology and biochemistry, and dysfunction/death of specific subsets of neurons in certain brain regions/neural circuits. Disease-defining pathology/biochemistry include the presence of extracellular toxic Ap42 peptides (oligomers) and intracellular protein aggregates of tau. Over the past several decades, investigators have taken advantage of advances in knowledge of the disease to design therapies for AD. For example, the demonstration of abnormalities of basal forebrain neurons (with cholinergic deficits in the cortex and hippocampus) led to the introduction of cholinesterase inhibitors for symptomatic treatments. Similarly, when information about involvement of glutamatergic systems in ventral-medial temporal lobes in AD was coupled with knowledge of roles of glutamate in excitotoxi-city, glutamate antagonists were tried as treatments. Building on several observations by Glenner and by many geneticists regarding Ap peptides and AD-related genes, investigators have generated a variety of models, particularly transgenic and knockout (KO) mice, that recapitulate some pathologies of AD or alter the expression of proteins critical to pathogenesis. Their models have proved to be of great value in understanding amyloid-related disease mechanisms, in identifying therapeutic targets, and in testing novel treatments. In this presentation, I will comment on these approaches, focusing on the roles of p- and y-secretase activities in amyloidogenesis and the potential of these enzymes as therapeutic targets for future clinical trials.

In familial AD, mutant genes encoding the amyloid precursor protein (APP) or presenilins (PS1 and 2) influence the levels and/or character of Ap peptides, which are generated via APP cleavages by the activities of p-secretase 1 (BACE1), and y-secretase (the PS, Nct, pen2, Aph-1 multi-protein complex). Mice overexpressingmutant APP/PS1 develop age-associated increases in brain levels of Ap42, Ap oligomers, neuritic plaques, and deficits in working memory. To gain insights into potential therapeutic targets, Dr. Phil Wong and colleagues targeted genes encoding proteins hypothesized to be critical for pro-amyloidogenic secretase activities. BACE1 -/- mice are viable and do not produce Ap; moreover, APPswe; PS1'E9; BACE1 -/- mice do not form Ap deposits or plaques; neither do they show memory deficits. Thus, BACE1, the neuronal p-secretase, is an attractive target for inhibition as part of an anti-amyloidogenic treat-

The Departments of Pathology1'Neurology2, Neuroscience3'andtheDivisionofNeuropathol-ogy, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205-2196, USA

Address correspondence to: Donald L. Price, M.D., The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205-2196, ment strategy. However, BACE1 null mice exhibit abnormalities during performance of tests of cognition and emotion; the former phenotype is rescued by overexpression of APP transgenes, indicating that APP processing plays a role in memory/cognition. Clinicians will have to be alert to mechanism-based side-effects related to inhibition of BACE1 activity. More recently, lentiviral RNAi injection strategies and conditional expression systems have been used to influence BACE1 activities and levels of amyloid at various stages of disease. Parallel studies of y-secretase have disclosed that PS1, Nicastrin (Nct), and Aph-1 (along with Pen-2) are key components of this complex and that lowering enzyme activity reduces production of Ap. However, these manipulations are also associated with adverse events, including problems with gastrointestinal cells and lymphocytes in adults. Significantly, although Nct~f~APPswe; PS1'E9 mice show reduced levels of Ap in the CNS, they also develop skin tumors, which reflects the importance of the Notch1 signaling pathway in suppression of neoplasms of the skin.

In summary, studies of AD and genetically engineered models of Ap amyloidosis (and the tauopathies), as well as investigations of other neurodegenerative diseases have greatly enhanced our understanding of pathogenic mechanisms, therapeutic targets, and potential mechanism-based treatments designed to benefit patients with AD and other neurological disorders.

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