P4‐249: NEURODEGENERATION PROGRESSES IN CONCERT WITH INTRANEURONAL Aβ AND TAU PATHOLOGY IN THE 3XTG‐AD MOUSE MODEL

Three pathologies define Alzheimer's disease (AD): Neurodegeneration, amyloid plaques, and neurofibrillary tangles. The exact order of these pathologies is not clearly defined. Mouse models used to study AD progression and prevention carry isolated symptoms and do not assemble the full human AD phenotype. The loss of neurons is present only in some disease models. We found now in the 3xTg-AD mouse model that the loss of neurons in the neocortex appears early together with the intraneuronal accumulation of Aβ and tau. Different age groups of 3xTg-AD mice were studied. Neuron loss was analyzed in paraformaldehyde fixed paraffin embedded brain sections by standard Nissl staining procedures and immunohistochemistry with the neuronal marker NeuN. Aβ pathology was assessed in the same sections by staining with anti-Aβ42 antibodies. Tau pathology was analyzed in sections stained with antibodies against human tau. Nissl staining showed large areas of pyknotic (apoptotic) neurons in different areas of the neocortex. In parallel sections the loss of NeuN staining was observed. This overlap indicated that a loss of NeuN positivity reflected areas of apoptotic neurons. Female and male mice showed intraneuronal Aβ in cortical neurons and areas of neuronal loss at 4 months of age. Some tau staining was found by immunohistochemistry in this age group. Extensive neuronal losses were observed in 14 and 17 months old males which did not show plaque staining, only intraneuronal Aβ deposits in hippocampus and neocortex. In contrast, females developed intraneuronal Aβ accumulation at 4-5 months of age and hippocampal plaques at 12-14 months of age. Preliminary results showed that neuronal loss was significantly lower in groups of 14 months old female mice which had received DNA Aβ42 immunotherapy. Findings in the 3xTg-AD mouse are modeling human AD pathology with start of Aβ storage in brain 25 years before and positive PET scans 15 years before the occurrence of symptoms. 3xTg-AD mice showed a similar time delay between cellular Aβ at five months and plaque Aβ at 12-14 months. Neurodegeneration, Aβ and tau are interacting early in an additive manner during AD progression, and an anti-Aβ immunotherapy has the potential to prevent neurodegeneration.