β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss

Abstract

Alzheimer disease is characterized by extracellular ␤-amyloid (A␤) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal A␤ associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral A␤ 1-42 that resulted in intracellular but not extracellular A␤ accumulations in the targeted rat primary motor cortex. Expression of intracellular A␤ 1-42 led to pathological changes seen in human Alzheimer disease brains, including cell death, inflammatory signs, activation of two Tau kinases, and Tau hyperphosphorylation. Promoting clearance of lentiviral A␤ 1-42 reversed these effects, demonstrating that intraneuronal A␤ 1-42 is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular A␤ 1-42 in a novel gene transfer animal model, which is a useful tool to study intraneuronal A␤ 1-42 -induced pathology in the absence of extracellular plaques. Targeted delivery of A␤ will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions. Alzheimer disease (AD)2 is the leading cause of dementia in the aging population. AD is characterized by widespread degeneration in the association cortices and the limbic system (1) accompanied by ␤-amyloid (A␤) deposition (2-4), the formation of intracellular neurofibrillary tangles of the Tau protein (5), and neuronal loss (6). A␤ 1-40 and A␤ 1-42 are produced intracellularly, and intraneuronal A␤ 1-42 accumulates in the brain of individuals with AD (7-11). Both intracellular A␤ and extracellular oligomeric A␤ have been implicated in AD pathology, but intracellular oligomeric species may act in the earlier stages of disease (12, 13). A␤ is produced intracellularly via the endosomal system and secretory pathways (14,15). In AD, endosomes in the pyramidal neurons are significantly bigger than control (16), and endocytic alterations can even happen before clinical symptoms and accumulation of extracellular A␤ deposits (17). In primary cultures of neurons overexpressing ␤-amyloid precursor protein, accumulation of intraneuronal A␤ induces neuronal apoptotic cell death (18). These findings suggest a crucial role for intracellular A␤ in the early stages of AD.Some studies showed that Tau is required for A␤ 1-42 to mediate detrimental effects, including toxicity in cell culture (19) and learning and memory impairments in amyloid precursor protein mice (20). Intracellular A␤ 1-42 accumulation precedes Tau pathology in triple transgenic mice exhibiting both plaque and tangle pathologies (13, 21), whereas ␤-amyloid pathology alone exacerbates Tau pathology (22). Removal of A␤ 1-42 significantly reduces Tau hyperphosphorylation in rodents (21, 23). These findings suggest a complex relationship between Tau and A␤ pathology in AD and other tauopathies.AD neuropathological changes also include astrogliosis and microglial cell proliferation (24 -27). Astrocytes and microglia are activated in areas of the brain affected by amyloid plaq...

Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models

“…Changes of 19 microglia morphology and astrogliosis surrounding pla-20 ques suggest inflammation in advanced stages of AD 21 (Akiyama et al, 2000). However, intracellular accumula- Rebeck et al, 2010). Furthermore, pre-plaque Ab acti-30 vates microglia and astrocytes and increases some 31 inflammatory markers (Rebeck et al, 2010), suggesting 32 that inflammation may not only be a response to CNS pla-33 que accumulation but also involve communication 34 between Ab-expressing neurons and the immune envi-35 ronment.…”

“…However, intracellular accumula- Rebeck et al, 2010). Furthermore, pre-plaque Ab acti-30 vates microglia and astrocytes and increases some 31 inflammatory markers (Rebeck et al, 2010), suggesting 32 that inflammation may not only be a response to CNS pla-33 que accumulation but also involve communication 34 between Ab-expressing neurons and the immune envi-35 ronment. Although microglia and astrocytes detect extra-36 cellular Ab through a number of sensors (Landreth and 37 Reed-Geaghan, 2009), intraneuronal Ab may induce 38 apoptosis, thus triggering neuronal signals to activate 39 microglia and astrocytes (Pereira et al, 2005) in soluble extracts from total brain lysates in 1Â STEN 229 buffer (see above).…”

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“…2), which can form membrane pores and dysfunctional ion channels, increasing proton leakage within mitochondria as a consequence (27) . In addition, astrocytes and microglia activated by amyloid deposits (neuro-inflammation) (28) increase circulating cytokine levels, thus adding to the catabolic state (29,30) .…”

The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

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