Over the past two decades, we have seen extraordinary progress in clinical discovery and preclinical research in the field of neurodegenerative disorders (Price et al. 2008). These investigations, including studies of animal models (Price et al. 2008), have provided important new directions for translation to the benefit of many patients with these illnesses. Studies of Alzheimer's disease (AD), the most common of these diseases of the central nervous system (CNS), illustrate the complementary contributions of advances in both clinical and basic research. Effective therapies for AD are a major unmet medical need because of its demographics (incidence/prevalence); morbidity/mortality rates; healthcare costs; paucity of mechanism-based treatments; and impact on affected individuals, caregivers, and society at large (Bishop et al. 2010; Blennow et al. 2006; Perrin et al. 2009; Querfurth and LaFerla 2010; Price et al. 2008). The clinical syndrome (i.e., cognitive and memory disturbances progressing to dementia in elderly persons) results from the dysfunction and death of neurons in specific brain regions and circuits critical for memory and cognition (Blennow etal. 2006; Buckner et al. 2008). The neuropathology of AD (Braak et al. 2006; Markesbery etal. 2006) includes the accumulation of extracellular β-pleated amyloid beta (Aβ) 42 peptides, which, as toxic oligomeric assemblies and/or aggregates (Cai et al. 2001; Price et al. 2008; Shankar et al. 2008; Wong et al. 2008), are at the cores of amyloid plaques (surrounded by swollen neurites). As described below, Aβ 42 is neurotoxic, particularly at synapses, and the plaques, at some level, represent sites of synaptic disconnection in the forebrain (Liu et al. 2008; Price et al. 2008). Within affected neurons, neurofibrillary tangles (NFT) are accumulations of misfolded tau (a microtubule-associated protein), the assembly of which into paired helical filaments (PHF) and, ultimately, into NFT (Ballatore et al. 2007; Goedert and Spillantini 2006; Mandkelkow et al. 2007), may be driven by the presence of β-sheet fragments of tau generated by cleavages in the microtubule binding domains of tau (Mocanu et al. 2008; Wang et al. 2007). At present, some investigators have hypothesized a fundamental pathogenic cascade that includes Aβ-mediated damage to synapses; alterations in the neuronal cytoskeleton; “dying back” of axons; and dysfunction of nerve cells (Liu et al. 2008). Eventually, those neurons exhibiting tau pathology die (Braak et al. 2006; de Calignon et al. 2010). The links between the amyloid/Aβ and NFT/tau abnormalities are not yet well defined.
|Original language||English (US)|
|Title of host publication||Translational Neuroscience|
|Subtitle of host publication||Applications in Psychiatry, Neurology, and Neurodevelopmental Disorders|
|Publisher||Cambridge University Press|
|Number of pages||19|
|State||Published - Jan 1 2012|
ASJC Scopus subject areas