• homozygotes are viable and fertile with no detectable abnormalities in morphology of the central or peripheral nervous systems

• mice show no significant motor deficits up to 12 months of age (J:169074)

• spatial working memory is not impaired (J:169074)

• 6 month old mutants exhibit slower visuospatial learning than control mice

• in the visuospatial re-learning test performed at 7, 8, 9, and 15 months of age, mutants exhibit a decrease in the speed of re-learning the task compared to controls

• however, mutants perform better than Tg(APPswe,PSEN1dE9)85Dbo mice on the visuospatial re-learning test at 9 and 18 months of age

• mutants do not exhibit Alzheimer's disease-related impairment in olfactory performance in tests based on an operant conditioning procedure and in tests based on a habituation/dishabituation procedure (J:172426)

• mice show reduced survival relative to wild-type, with almost 100% mortality observed by 16 months

• accelerated mortality is observed before 3 months of age (after 1 month of age) compared to wild-type or Tg(Thy1-MAPT*)30Schd single mutant animals

• at 12 months, neuronal cell numbers are similar in the hippocampal CA1-CA3 sectors and spinal cord to those in Tg(Thy1-MAPT*)30Schd mice; volumes of brain, cortex, hippocampal formation and cervical spinal cord are similar (J:169074)

• mice show significantly increased proportion of insoluble tau protein relative to sarkosyl-soluble tau compared to Tg(Thy1-MAPT*)30Schd single mutants

• soluble tau shows decreased phosphorylation compared to single transgenics, while insoluble tau displays significantly elevated phosporylation levels

• GSK-3 kinase activation in the brain is increased compared to wild-type and single mutants

• NFTs are detected in the hippocampus, cortex, subcortical areas, brainstem, and spinal cord at 12 months, while no tangles are found in wild-type or Mapt mutants

• density (number) of NFTs is significantly increased in the hippocampus (subiculum and CA1 region) compared to Tg(Thy1-MAPT*)30Schd single mutants, but is similar between lines in the spinal cord

• mice display axonal loss and reduction in cross-sectional area and axon density in the sciatic nerve compared to wild-type or Mapt mutants

• mice develop numerous pericaryal rounded inclusions in the spinal cord; these are composed to abnormal filaments mixed with abundant neurofilaments; these are more numerous than seen in single transgenics

• in Y-maze tests, percentage of alternations observed is not significantly different from single transgenics, Mapt mutants or wild-type at 3-6 months of age (J:169074)

• mice show a progressive motor deficit, significant from 6 to 12 months compared to wild-type or Mapt mutants; impairment is much more severe than in Tg(Thy1-MAPT*)30Schd single mutants

• phosphorylated tau accumulates in neuronal cell bodies and dendrites of the hippocampus and neocortex as early as 3 months of age

• in particular, accumulations occur in entorhinal cortex, ventromedial hypothalamus, medial septum and the nucleus of the horizontal limb of the diagonal band

• increase in tau phosphorylation occurs at serine 202, threonine 231 and serine 235 as determined by immunoblot

• tau aggregates in the proximal dendrites have an average width of 15 nm and are not densely packed

• insoluble tau is present in both 2 and 9 month old mice

• paired helical filaments are observed in 9, 12 and 14 month old mice

• cells in the cortex and hippocampus appear irregularly shaped, often with distorted processes in 13 month old mice

• splenic red pulp is largely obliterated

• splenic white pulp contains follicles that are larger and more irregular in shape than normal follicles and are often fused with adjacent follicles

• splenic red pulp is largely obliterated

• splenic white pulp contains follicles that are larger and more irregular in shape than normal follicles and are often fused with adjacent follicles

• some mutants older than 18 months exhibit amyloid deposits in the spleen, kidneys, liver, ovary and/or heart

• amyloid is deposited concentrically in the perifollicular sheath, partly or completely encircling the follicles in the spleen

• in the liver, amyloid deposit is in the walls of sinusoids or central veins

• in the kidney, amyloid deposits are seen in the glomeruli

• amyloid deposits in the heart are not composed of amyloid-beta peptide, but rather amyloid A

• kidney glomeruli are dilated probably due to obstruction from the amyloid in the lumen or walls of medullary tubules especially in the papilla

• malignant lymphoma in the spleen and lymph nodes are seen in some mutants

• megakaryocytes are numerous is some spleens, suggesting a relation to megakaryocytic leukemia

• splenic architecture is replaced by proliferated immature mononuclear cells arranged in follicular aggregates indicating follicular lymphoma