Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.

Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid ␤ peptide, A␤42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, A␤ peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717 V3 F )-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased A␤ production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of A␤ that is independent of plaque formation.Alzheimer's disease (AD) is a progressive dementing illness in which the brain becomes littered with neuritic amyloid plaques. These plaques are associated with degenerating neuronal processes and consist primarily of fibrillar aggregates of the amyloid ␤ peptide, A␤. A␤ is derived from the amyloid protein precursor (APP), presumably via proteolytic cleavage of APP by ␤-and ␥-secretases (1). The predominant forms of A␤ are 40 (A␤40) or 42 (A␤42) amino acids in length (2). A␤42 and A␤40 appear to be generated in different intracellular compartments, and A␤42 has a greater propensity to selfaggregate into insoluble fibrils than A␤40 (3, 4). Various point mutations in three distinct genes (APP, presenilin 1, presenilin 2) have been linked to autosomal dominant forms of familial AD (FAD). Notably, all of these mutations increase the production of A␤42 (5).Although A␤ has been shown to be neurotoxic in cell culture (6-8), a causal role for A␤ in widespread neuronal degeneration in vivo remains speculative. A particularly controversial question concerns whether A␤-induced neurotoxicity requires deposition of aggregated A␤ into plaques (9-13). Transgenic mice in which full-length FAD-mutant APPs and A␤ are coexpressed at high levels develop typical neuritic amyloid plaques (14-17). However, loss of neurons so far has been identified in only one of these models (18) whereas two others showed no significant neuronal loss despite extensive cerebral A␤ deposition (19,20). No electrophysiological studies have been reported in these models.In the current study, we investigated in transgenic mice what early effects neuronal expression of full-length, FAD-mutant human APP has on the anatomy and physiology of the hippocampus, a central nervous system structure considered crucial for learning and memory. Our study demonstrates that the development ...

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.epilepsy | plasticity | therapy | dementia | hyperexcitability

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.