Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-␤ peptides (A␤) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D 28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of A␤1-42 but not with the amount of A␤ deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between A␤-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.

Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminaltruncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxylterminal-cleaved product, apoE4(⌬272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silverpositive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6 -7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits.H uman apolipoprotein (apo) E, a 34-kDa protein composed of 299 amino acids, occurs as three major isoforms, apoE2, apoE3, and apoE4 (1-4). ApoE4 is a major risk or susceptibility factor for Alzheimer's disease (AD) (5-7). The apoE4 allele, which is found in 40-65% of cases of sporadic and familial AD, increases the occurrence and lowers the age of onset of the disease (7,8).Biochemical, cell biological, and transgenic animal studies have suggested several potential mechanisms to explain apoE4's contribution to the pathogenesis of AD. These include the modulation of the deposition and clearance of amyloid ␤ peptides and the formation of plaques (9-15), impairment of the antioxidative defense system (16), dysregulation of neuronal signaling pathways (17), disruption of cytoskeletal structure and function (18,19), and altered phosphorylation of tau and the formation of neurofibrillary tangles (NFTs) (20-23). However, the mechanisms of these apoE4-mediated detrimental effects are still largely unknown, and it is not known which are the primary effects and which are subsequent or downstream effects.The neuropathological hallmarks of AD include extracellular amyloid plaques and intracellular NFTs in the brain (24-27). The plaques consist primarily of amyloid ␤ peptides (24-26). The NFTs are composed largely of the highly phosphorylated microtubule-associated protein tau (p-tau) (25) and, to a lesser extent, of phosphorylated neurofilaments (28, 29). Both amyloid plaques and NFTs contain apoE (5, 30, 31); however, the role of apoE in the pathogenesis of these two lesions is uncertain. Histopathological and behavioral analyses of transgenic mice expressing different human apoE isoforms in the brain have revealed clear evi...

Alzheimer's disease (AD) is associated with accumulations of amyloid-␤ (A␤) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2 ϩ/Ϫ ) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to ϳ50% of that in Sod2 wild-type (Sod2 ϩ/ϩ ) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/A␤ expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/A␤-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor B. These results suggest that Sod2 protects the aging brain against hAPP/A␤-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.