Accumulation of amyloid-β (Aβ) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is
thought to be a later downstream event. It is now well established that Aβ exists as monomers, oligomers, and fibrils. To
study the temporal profile of Aβ oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation
of plaques and tangles and cognitive impairments. We show that SDS-resistant Aβ oligomers accumulate in an age-dependent fashion,
and we present evidence to show that oligomerization of Aβ appears to first occur intraneuronally. Finally, we show that a
single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear Aβ pathology, and more importantly,
tau pathology. Therefore, Aβ oligomers may play a role in the induction of tau pathology, making the interference of Aβ oligomerization
a valid therapeutic target.
"Lastly, enhancement of Ab clearance in transgenic mouse models with overexpression of mutant APP, but with no tau pathology, has been shown to improve cognitive function in mice (Lemere, 2013; Wisniewski and Sigurdsson, 2010). Subsequent work also has revealed that the inhibition of Ab in animal models with overexpression of mutant APP and tau not only prevents the development of tau-related aggregates but also improves cognitive deficits (Blurton-Jones and Laferla, 2006; McKee et al., 2008; Oddo et al., 2006). "
"Additionally, Aβ 1-42 oligomers have been shown to contribute to neurofibrillary tangle formation. In the triple transgenic mouse model of AD (3xTg-AD), Aβ deposition precedes tau pathology by several months , with intrahippocampal injection of an anti-Aβ oligomer antibody reducing both Aβ and tau pathology . Recent evaluations have also shown that treatment of cell cultures with soluble Aβ dimers isolated from AD cortical tissue directly induces tau hyperphosphorylation and neuritic dystrophy . "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive loss in memory and cognitive abilities. One of the key pathologic features of AD is the accumulation of beta amyloid (Aβ). Somatostatin has been shown to regulate neuronal neprilysin activity, a key enzyme involved in Aβ catabolism. The actions of somatostatin are mediated through somatostatin receptors 1-5. The somatostatin subtype-4 receptor (sst 4) is expressed in key regions of the brain impacted by AD. Thus, sst 4 agonists may serve as disease modifying agents (i.e., preventative), enhancing enzymatic activity and decreasing neurotoxic Aβ species within key brain regions of AD patients. This chapter will address the viability of such sst 4 agonists within the context of AD therapy, in conjunction with strategies for design, synthesis, and recognition at the macromolecular level.
Frontiers in Drug Design & Discovery, Edited by Atta-ur-Rahman and Mohammad Iqbal Choudhary, 01/2014: pages 566-597; Bentham Science.
"So far, the peripheral immune systems of AD and MCI animal models have not been systematically explored in longitudinal studies. The triple-transgenic, 3xTg-AD (AD) substrain is one of several wellestablished murine models because it mimics several key aspects of AD neuropathology: 1) A␤ plaques and neurofibrillary pathology develop in AD-relevant brain regions, such as the hippocampus, cortex, and amygdala ; 2) plaque pathology precedes tangle formation, and plaques consist of the longer, more amyloidogenic A␤ 42 ; 3) the pattern of conformational and phosphorylation changes that the tau protein undergoes parallels the sequence in the human AD brain; 4) selective loss of nicotinic ␣7 receptors in the hippocampus and cortex    . In conjunction with an early, intra-neuronal accumulation of A␤, these mice also develop deficits in long-term potentiation, paired-pulse facilitation, and long-term memory  . "
[Show abstract][Hide abstract] ABSTRACT: Background: Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective: The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods: A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results: Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired "cognitive" flexibility in the first six months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion: The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.
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