No abstract

Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.

Amyloid-β (Aβ) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either β-or γ-secretase, enzymes required for production of Aβ from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.TBI is the leading cause of mortality and disability among young individuals in developed countries, and globally the incidence of TBI is rising sharply 1 . TBI is a disease process, with an initial injury that induces biochemical and cellular changes that contribute to continuing neuronal damage and death over time. This continuing damage is known as secondary injury, and multiple apoptotic and inflammatory pathways are activated as part of this process (for reviews, see refs. 2,3 ). TBI is a major risk factor for the development of Alzheimer's disease 4,5 , and post-mortem studies show that 30% of TBI fatalities have Aβ deposits 6,7 . Remarkably, these deposits may occur less than 1 d after injury 8 . Not only does Aβ accumulate after TBI 9,10 , but also do the necessary APP enzymes responsible for Aβ production: β-APPcleaving enzyme-1 (BACE1) and presenilin-1, a γ-secretase complex protein [11][12][13][14] . Although the role of the APP secretases in secondary injury is unknown, multiple lines of evidence show that Aβ can cause cell death, activate inflammatory pathways [15][16][17][18] and prime proapoptotic pathways for activation by other insults 19 . The APP secretases may also be directly involved in secondary injury, as over-expressed BACE1 alone has been shown to cause neuronal cell loss in the absence of Aβ accumulation 20 . These facts make the APP secretases a potential therapeutic target for TBI.In our initial experiments, we characterized the TBI-induced protein changes in a nontransgenic mouse. We performed TBI by controlled cortical impact (CCI) of the left parietal cortex. This model induces both necrotic and apoptotic cell death, causing brain lesion and the development of behavioral deficits 21 . It has recently been reported that interstitial fluid Aβ concentrations correlate with neurological function in the injured human brain, with Aβ accumulating as neurological function improved in the days after trauma 22 . Exposure to experimental TBI resulted in accumulation of endogenous mouse Aβ x-40 peptide in the ipsilateral cortex within 1 d (Fig. 1a). Aβ levels increased by almost 120% at 3 d after injury before normalizing by 7 d (Fig. 1a) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBace1 and presenilin-1 (Fig. 1b), as has been previously reported in other animal models and humans 9-14 . Soluble APP-α, which is purported to be neuroprotective 23 , was also increased after injury. Functionally, this model of TBI causes deficits in fine motor coordination (beam walk test, Supplementary Fig. 1a online) in the absence of gross motor def...

Plaques containing beta-amyloid (Abeta) peptides are one of the pathological features of Alzheimer's disease, and the reduction of Abeta is considered a primary therapeutic target. Amyloid clearance by anti-Abeta antibodies has been reported after immunization, and recent data have shown that the antibodies may act as a peripheral sink for Abeta, thus altering the periphery/brain dynamics. Here we show that peripheral treatment with an agent that has high affinity for Abeta (gelsolin or GM1) but that is unrelated to an antibody or immune modulator reduced the level of Abeta in the brain, most likely because of a peripherally acting effect. We propose that in general, compounds that sequester plasma Abeta could reduce or prevent brain amyloidosis, which would enable the development of new therapeutic agents that are not limited by the need to penetrate the brain or evoke an immune response.